diff --git a/src/coreclr/jit/gentree.cpp b/src/coreclr/jit/gentree.cpp
index 9154da487bd1fa..0ab30837412ff7 100644
--- a/src/coreclr/jit/gentree.cpp
+++ b/src/coreclr/jit/gentree.cpp
@@ -14485,6 +14485,23 @@ GenTree* Compiler::gtFoldExprSpecial(GenTree* tree)
         case GT_EQ:
         case GT_NE:
         {
+            // For "obj ==/!= null" we can fold the comparison to true/false if VM tells us that the object cannot
+            // be non-null. Example: "obj == null" -> true if obj's type is FooCls and FooCls is an abstract class
+            // without subclasses.
+            //
+            // IsTargetAbi check is not necessary here, but it improves TP for runtimes where this optimization is
+            // not possible anyway.
+            if ((val == 0) && op->TypeIs(TYP_REF) && IsTargetAbi(CORINFO_NATIVEAOT_ABI))
+            {
+                bool                 isExact, isNonNull;
+                CORINFO_CLASS_HANDLE opCls = gtGetClassHandle(op, &isExact, &isNonNull);
+                if ((opCls != NO_CLASS_HANDLE) && (info.compCompHnd->getExactClasses(opCls, 0, nullptr) == 0))
+                {
+                    op = gtWrapWithSideEffects(NewMorphedIntConNode(tree->OperIs(GT_EQ) ? 1 : 0), op, GTF_ALL_EFFECT);
+                    goto DONE_FOLD;
+                }
+            }
+
             // Optimize boxed value classes; these are always false.  This IL is
             // generated when a generic value is tested against null:
             //     <T> ... foo(T x) { ... if ((object)x == null) ...
diff --git a/src/coreclr/tools/Common/Compiler/DevirtualizationManager.cs b/src/coreclr/tools/Common/Compiler/DevirtualizationManager.cs
index 5574a9f8aa100f..7d1c3be1de42a9 100644
--- a/src/coreclr/tools/Common/Compiler/DevirtualizationManager.cs
+++ b/src/coreclr/tools/Common/Compiler/DevirtualizationManager.cs
@@ -208,6 +208,12 @@ protected virtual MethodDesc ResolveVirtualMethod(MethodDesc declMethod, DefType
         /// </summary>
         public virtual bool CanReferenceConstructedMethodTable(TypeDesc type) => true;
 
+        /// <summary>
+        /// Gets a value indicating whether it might be possible that the interface type is implemented by a constructed type data structure
+        /// in this compilation. Note that the MethodTable for the interface itself could still be optimized away.
+        /// </summary>
+        public virtual bool CanInterfaceBeImplementedByConstructedMethodTable(TypeDesc type) => true;
+
         /// <summary>
         /// Gets a value indicating whether a (potentially canonically-equlivalent) constructed MethodTable could
         /// exist. This is similar to <see cref="CanReferenceConstructedMethodTable"/>, but will return true
@@ -215,6 +221,15 @@ protected virtual MethodDesc ResolveVirtualMethod(MethodDesc declMethod, DefType
         /// </summary>
         public virtual bool CanReferenceConstructedTypeOrCanonicalFormOfType(TypeDesc type) => true;
 
+        /// <summary>
+        /// Gets a value indicating whether it might be possible that the interface type is implemented by a constructed type data structure
+        /// in this compilation. Note that the MethodTable for the interface itself could still be optimized away.
+        /// Similar to <see cref="CanInterfaceBeImplementedByConstructedMethodTable"/> but will return true for
+        /// IInterface&lt;__Canon&gt; if IInterface&lt;String&gt; could be implemented.
+        /// </summary>
+        public virtual bool CanInterfaceOrCanonicalFormOfItBeImplementedByConstructedMethodTable(TypeDesc type) => true;
+
+
         public virtual TypeDesc[] GetImplementingClasses(TypeDesc type) => null;
 #endif
     }
diff --git a/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/Compilation.cs b/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/Compilation.cs
index 6a542d8d00a748..4673b0f7b18421 100644
--- a/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/Compilation.cs
+++ b/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/Compilation.cs
@@ -108,11 +108,21 @@ public bool CanReferenceConstructedMethodTable(TypeDesc type)
             return NodeFactory.DevirtualizationManager.CanReferenceConstructedMethodTable(type.NormalizeInstantiation());
         }
 
+        public bool CanInterfaceBeImplementedByConstructedMethodTable(TypeDesc type)
+        {
+            return NodeFactory.DevirtualizationManager.CanInterfaceBeImplementedByConstructedMethodTable(type.NormalizeInstantiation());
+        }
+
         public bool CanReferenceConstructedTypeOrCanonicalFormOfType(TypeDesc type)
         {
             return NodeFactory.DevirtualizationManager.CanReferenceConstructedTypeOrCanonicalFormOfType(type.NormalizeInstantiation());
         }
 
+        public bool CanInterfaceOrCanonicalFormOfItBeImplementedByConstructedMethodTable(TypeDesc type)
+        {
+            return NodeFactory.DevirtualizationManager.CanInterfaceOrCanonicalFormOfItBeImplementedByConstructedMethodTable(type.NormalizeInstantiation());
+        }
+
         public DelegateCreationInfo GetDelegateCtor(TypeDesc delegateType, MethodDesc target, TypeDesc constrainedType, bool followVirtualDispatch)
         {
             // If we're creating a delegate to a virtual method that cannot be overridden, devirtualize.
diff --git a/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/ILScanner.cs b/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/ILScanner.cs
index 4d9328f1a34eef..954ae7b92b256e 100644
--- a/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/ILScanner.cs
+++ b/src/coreclr/tools/aot/ILCompiler.Compiler/Compiler/ILScanner.cs
@@ -438,6 +438,8 @@ private sealed class ScannedDevirtualizationManager : DevirtualizationManager
             private HashSet<TypeDesc> _constructedMethodTables = new HashSet<TypeDesc>();
             private HashSet<TypeDesc> _canonConstructedMethodTables = new HashSet<TypeDesc>();
             private HashSet<TypeDesc> _canonConstructedTypes = new HashSet<TypeDesc>();
+            private HashSet<TypeDesc> _implementedInterfaces = new HashSet<TypeDesc>();
+            private HashSet<TypeDesc> _canonImplementedInterfaces = new HashSet<TypeDesc>();
             private HashSet<TypeDesc> _unsealedTypes = new HashSet<TypeDesc>();
             private Dictionary<TypeDesc, HashSet<TypeDesc>> _implementators = new();
             private HashSet<TypeDesc> _disqualifiedTypes = new();
@@ -507,6 +509,13 @@ public ScannedDevirtualizationManager(NodeFactory factory, ImmutableArray<Depend
                                     {
                                         RecordImplementation(baseInterface, type);
                                     }
+
+                                    if (_implementedInterfaces.Add(baseInterface))
+                                    {
+                                        TypeDesc canonBaseInterface = baseInterface.ConvertToCanonForm(CanonicalFormKind.Specific);
+                                        if (baseInterface != canonBaseInterface)
+                                            _canonImplementedInterfaces.Add(canonBaseInterface);
+                                    }
                                 }
 
                                 // Record all base types of this class
@@ -729,6 +738,13 @@ public override bool CanReferenceConstructedMethodTable(TypeDesc type)
                 return _constructedMethodTables.Contains(type);
             }
 
+            public override bool CanInterfaceBeImplementedByConstructedMethodTable(TypeDesc type)
+            {
+                Debug.Assert(type.NormalizeInstantiation() == type);
+                Debug.Assert(type.IsInterface);
+                return _implementedInterfaces.Contains(type);
+            }
+
             public override bool CanReferenceConstructedTypeOrCanonicalFormOfType(TypeDesc type)
             {
                 Debug.Assert(type.NormalizeInstantiation() == type);
@@ -736,6 +752,13 @@ public override bool CanReferenceConstructedTypeOrCanonicalFormOfType(TypeDesc t
                 return _constructedMethodTables.Contains(type) || _canonConstructedMethodTables.Contains(type);
             }
 
+            public override bool CanInterfaceOrCanonicalFormOfItBeImplementedByConstructedMethodTable(TypeDesc type)
+            {
+                Debug.Assert(type.NormalizeInstantiation() == type);
+                Debug.Assert(type.IsInterface);
+                return _implementedInterfaces.Contains(type) || _canonImplementedInterfaces.Contains(type);
+            }
+
             public override TypeDesc[] GetImplementingClasses(TypeDesc type)
             {
                 if (_disqualifiedTypes.Contains(type))
diff --git a/src/coreclr/tools/aot/ILCompiler.RyuJit/JitInterface/CorInfoImpl.RyuJit.cs b/src/coreclr/tools/aot/ILCompiler.RyuJit/JitInterface/CorInfoImpl.RyuJit.cs
index b4933c28b25afc..293a9df6a835d3 100644
--- a/src/coreclr/tools/aot/ILCompiler.RyuJit/JitInterface/CorInfoImpl.RyuJit.cs
+++ b/src/coreclr/tools/aot/ILCompiler.RyuJit/JitInterface/CorInfoImpl.RyuJit.cs
@@ -2244,8 +2244,25 @@ private bool CanNeverHaveInstanceOfSubclassOf(TypeDesc type)
             if (!ConstructedEETypeNode.CreationAllowed(type))
                 return false;
 
+            // TODO: rather conservative
+            if (type.HasVariance)
+                return false;
+
             TypeDesc canonType = type.ConvertToCanonForm(CanonicalFormKind.Specific);
 
+            // Interface optimization may be able to remove MethodTable of interfaces if they were never actually
+            // used to call/cast. Since getExactClasses can be called for things like "is a location of this
+            // type ever going to be non-null", we need to make sure the ability to optimize the interface MethodTable away
+            // doesn't lead to saying "this will always be null".
+            if (type.IsInterface)
+            {
+                if (_compilation.CanInterfaceOrCanonicalFormOfItBeImplementedByConstructedMethodTable(type)
+                    || (type != canonType && _compilation.CanInterfaceBeImplementedByConstructedMethodTable(canonType)))
+                {
+                    return false;
+                }
+            }
+
             // If we don't have a constructed MethodTable for the exact type or for its template,
             // this type or any of its subclasses can never be instantiated.
             return !_compilation.CanReferenceConstructedTypeOrCanonicalFormOfType(type)
diff --git a/src/tests/nativeaot/SmokeTests/TrimmingBehaviors/DeadCodeElimination.cs b/src/tests/nativeaot/SmokeTests/TrimmingBehaviors/DeadCodeElimination.cs
index 032c3a07d7dea6..c1181638f2aef5 100644
--- a/src/tests/nativeaot/SmokeTests/TrimmingBehaviors/DeadCodeElimination.cs
+++ b/src/tests/nativeaot/SmokeTests/TrimmingBehaviors/DeadCodeElimination.cs
@@ -28,6 +28,7 @@ public static int Run()
         TestTypeIsEnum.Run();
         TestTypeIsValueType.Run();
         TestBranchesInGenericCodeRemoval.Run();
+        TestCanBeNonNull.Run();
         TestUnmodifiableStaticFieldOptimization.Run();
         TestUnmodifiableInstanceFieldOptimization.Run();
         TestGetMethodOptimization.Run();
@@ -716,6 +717,105 @@ public static void Run()
         }
     }
 
+    class TestCanBeNonNull
+    {
+        interface INever1;
+        interface INever2<T>;
+        interface INever3<T>;
+        interface INever3_Variant<in T>;
+
+        class ImplementsINever3Object : INever3<object>;
+        class ImplementsINever3_VariantObject : INever3_Variant<object>;
+
+        interface IImplemented;
+        class Implements : IImplemented;
+
+        class Canary1;
+        class Canary2;
+        class Canary3;
+        class Canary4;
+        class Canary5;
+
+        [MethodImpl(MethodImplOptions.NoInlining)]
+        static object AcceptINever(INever1 inst)
+        {
+            if (inst != null)
+            {
+                return new Canary1();
+            }
+            return null;
+        }
+
+        [MethodImpl(MethodImplOptions.NoInlining)]
+        static object AcceptINever2<T>(INever2<T> inst)
+        {
+            if (inst != null)
+            {
+                return new Canary2();
+            }
+            return null;
+        }
+
+        [MethodImpl(MethodImplOptions.NoInlining)]
+        static object AcceptIImplemented(IImplemented inst)
+        {
+            if (inst != null)
+            {
+                return new Canary3();
+            }
+            return null;
+        }
+
+        [MethodImpl(MethodImplOptions.NoInlining)]
+        static object AcceptINever3String(INever3<string> inst)
+        {
+            if (inst != null)
+            {
+                return new Canary4();
+            }
+            return null;
+        }
+
+        [MethodImpl(MethodImplOptions.NoInlining)]
+        static object AcceptINever3_VariantString(INever3_Variant<string> inst)
+        {
+            if (inst != null)
+            {
+                return new Canary5();
+            }
+            return null;
+        }
+
+        public static void Run()
+        {
+            if (AcceptINever(null) != null)
+                throw new Exception();
+#if !DEBUG
+            ThrowIfPresentWithUsableMethodTable(typeof(TestCanBeNonNull), nameof(Canary1));
+#endif
+
+            if (AcceptINever2<object>(null) != null)
+                throw new Exception();
+#if !DEBUG
+            ThrowIfPresentWithUsableMethodTable(typeof(TestCanBeNonNull), nameof(Canary2));
+#endif
+
+            if (AcceptIImplemented(new Implements()) == null)
+                throw new Exception();
+            ThrowIfNotPresent(typeof(TestCanBeNonNull), nameof(Canary3));
+
+            new ImplementsINever3Object().ToString();
+            AcceptINever3String(null);
+#if !DEBUG
+            ThrowIfPresentWithUsableMethodTable(typeof(TestCanBeNonNull), nameof(Canary4));
+#endif
+
+            if (AcceptINever3_VariantString(new ImplementsINever3_VariantObject()) == null)
+                throw new Exception();
+            ThrowIfNotPresent(typeof(TestCanBeNonNull), nameof(Canary5));
+        }
+    }
+
     class TestUnmodifiableStaticFieldOptimization
     {
         static class ClassWithNotReadOnlyField