diff --git a/mypyc/ir/class_ir.py b/mypyc/ir/class_ir.py
index 0a56aaf5d101..487da48ef4fd 100644
--- a/mypyc/ir/class_ir.py
+++ b/mypyc/ir/class_ir.py
@@ -237,6 +237,16 @@ def __repr__(self) -> str:
     def fullname(self) -> str:
         return f"{self.module_name}.{self.name}"
 
+    @property
+    def allow_interpreted_subclasses(self) -> bool:
+        return (
+            self._allow_interpreted_subclasses or not self.is_ext_class and not self.is_final_class
+        )
+
+    @allow_interpreted_subclasses.setter
+    def allow_interpreted_subclasses(self, value: bool) -> None:
+        self._allow_interpreted_subclasses = value
+
     def real_base(self) -> ClassIR | None:
         """Return the actual concrete base class, if there is one."""
         if len(self.mro) > 1 and not self.mro[1].is_trait:
@@ -345,11 +355,10 @@ def subclasses(self) -> set[ClassIR] | None:
             return None
         result = set(self.children)
         for child in self.children:
-            if child.children:
-                child_subs = child.subclasses()
-                if child_subs is None:
-                    return None
-                result.update(child_subs)
+            child_subs = child.subclasses()
+            if child_subs is None:
+                return None
+            result.update(child_subs)
         return result
 
     def concrete_subclasses(self) -> list[ClassIR] | None:
@@ -381,7 +390,7 @@ def serialize(self) -> JsonDict:
             "is_final_class": self.is_final_class,
             "inherits_python": self.inherits_python,
             "has_dict": self.has_dict,
-            "allow_interpreted_subclasses": self.allow_interpreted_subclasses,
+            "allow_interpreted_subclasses": self._allow_interpreted_subclasses,
             "needs_getseters": self.needs_getseters,
             "_serializable": self._serializable,
             "builtin_base": self.builtin_base,
diff --git a/mypyc/irbuild/ll_builder.py b/mypyc/irbuild/ll_builder.py
index 37f2add4abbd..9a6ace7fbb2d 100644
--- a/mypyc/irbuild/ll_builder.py
+++ b/mypyc/irbuild/ll_builder.py
@@ -695,8 +695,8 @@ def isinstance_native(self, obj: Value, class_ir: ClassIR, line: int) -> Value:
         """Fast isinstance() check for a native class.
 
         If there are three or fewer concrete (non-trait) classes among the class
-        and all its children, use even faster type comparison checks `type(obj)
-        is typ`.
+        and all its children, and none of them allow interpreted subclasses, use
+        even faster type comparison checks `type(obj) is typ`.
         """
         concrete = all_concrete_classes(class_ir)
         if concrete is None or len(concrete) > FAST_ISINSTANCE_MAX_SUBCLASSES + 1:
diff --git a/mypyc/test-data/irbuild-classes.test b/mypyc/test-data/irbuild-classes.test
index 94e89f276eeb..d90d52040394 100644
--- a/mypyc/test-data/irbuild-classes.test
+++ b/mypyc/test-data/irbuild-classes.test
@@ -2852,3 +2852,40 @@ class InvalidKwarg:
 @mypyc_attr(str())  # E: All "mypyc_attr" positional arguments must be string literals.
 class InvalidLiteral:
     pass
+
+[case testIsInstanceInterpretedSubclasses]
+from typing import Any
+from mypy_extensions import mypyc_attr
+
+@mypyc_attr(native_class=False)
+class NonNative:
+    pass
+
+@mypyc_attr(allow_interpreted_subclasses=True)
+class InterpSubclasses:
+    pass
+
+def isinstance_nonnative(x: Any) -> bool:
+    return isinstance(x, NonNative)
+def isinstance_interpreted_subclasses(x: Any) -> bool:
+    return isinstance(x, InterpSubclasses)
+[out]
+def isinstance_nonnative(x):
+    x, r0 :: object
+    r1 :: ptr
+    r2 :: object
+    r3 :: bit
+L0:
+    r0 = __main__.NonNative :: type
+    r1 = get_element_ptr x ob_type :: PyObject
+    r2 :: borrow load_mem r1 :: builtins.object*
+    keep_alive x
+    r3 :: r2 == r0
+    return r3
+def isinstance_interpreted_subclasses(x):
+    x, r0 :: object
+    r1 :: bool
+L0:
+    r0 = __main__.InterpSubclasses :: type
+    r1 = CPy_TypeCheck(x, r0)
+    return r1