diff --git a/crates/ty_python_semantic/resources/mdtest/call/builtins.md b/crates/ty_python_semantic/resources/mdtest/call/builtins.md
index b7415de8b4..f32c007c1c 100644
--- a/crates/ty_python_semantic/resources/mdtest/call/builtins.md
+++ b/crates/ty_python_semantic/resources/mdtest/call/builtins.md
@@ -152,7 +152,8 @@ s = SubclassOfA()
 reveal_type(isinstance(s, SubclassOfA))  # revealed: Literal[True]
 reveal_type(isinstance(s, A))  # revealed: Literal[True]
 
-def _(x: A | B):
+def _(x: A | B, y: list[int]):
+    reveal_type(isinstance(y, list))  # revealed: Literal[True]
     reveal_type(isinstance(x, A))  # revealed: bool
 
     if isinstance(x, A):
diff --git a/crates/ty_python_semantic/resources/mdtest/exhaustiveness_checking.md b/crates/ty_python_semantic/resources/mdtest/exhaustiveness_checking.md
index 713cd05b2d..360938cd13 100644
--- a/crates/ty_python_semantic/resources/mdtest/exhaustiveness_checking.md
+++ b/crates/ty_python_semantic/resources/mdtest/exhaustiveness_checking.md
@@ -238,3 +238,103 @@ def match_non_exhaustive(x: A | B | C):
             # this diagnostic is correct: the inferred type of `x` is `B & ~A & ~C`
             assert_never(x)  # error: [type-assertion-failure]
 ```
+
+## `isinstance` checks with generics
+
+```toml
+[environment]
+python-version = "3.12"
+```
+
+```py
+from typing import assert_never
+
+class A[T]: ...
+class ASub[T](A[T]): ...
+class B[T]: ...
+class C[T]: ...
+class D: ...
+class E: ...
+class F: ...
+
+def if_else_exhaustive(x: A[D] | B[E] | C[F]):
+    if isinstance(x, A):
+        pass
+    elif isinstance(x, B):
+        pass
+    elif isinstance(x, C):
+        pass
+    else:
+        # TODO: both of these are false positives (https://github.com/astral-sh/ty/issues/456)
+        no_diagnostic_here  # error: [unresolved-reference]
+        assert_never(x)  # error: [type-assertion-failure]
+
+# TODO: false-positive diagnostic (https://github.com/astral-sh/ty/issues/456)
+def if_else_exhaustive_no_assertion(x: A[D] | B[E] | C[F]) -> int:  # error: [invalid-return-type]
+    if isinstance(x, A):
+        return 0
+    elif isinstance(x, B):
+        return 1
+    elif isinstance(x, C):
+        return 2
+
+def if_else_non_exhaustive(x: A[D] | B[E] | C[F]):
+    if isinstance(x, A):
+        pass
+    elif isinstance(x, C):
+        pass
+    else:
+        this_should_be_an_error  # error: [unresolved-reference]
+
+        # this diagnostic is correct: the inferred type of `x` is `B[E] & ~A[D] & ~C[F]`
+        assert_never(x)  # error: [type-assertion-failure]
+
+def match_exhaustive(x: A[D] | B[E] | C[F]):
+    match x:
+        case A():
+            pass
+        case B():
+            pass
+        case C():
+            pass
+        case _:
+            # TODO: both of these are false positives (https://github.com/astral-sh/ty/issues/456)
+            no_diagnostic_here  # error: [unresolved-reference]
+            assert_never(x)  # error: [type-assertion-failure]
+
+# TODO: false-positive diagnostic (https://github.com/astral-sh/ty/issues/456)
+def match_exhaustive_no_assertion(x: A[D] | B[E] | C[F]) -> int:  # error: [invalid-return-type]
+    match x:
+        case A():
+            return 0
+        case B():
+            return 1
+        case C():
+            return 2
+
+def match_non_exhaustive(x: A[D] | B[E] | C[F]):
+    match x:
+        case A():
+            pass
+        case C():
+            pass
+        case _:
+            this_should_be_an_error  # error: [unresolved-reference]
+
+            # this diagnostic is correct: the inferred type of `x` is `B[E] & ~A[D] & ~C[F]`
+            assert_never(x)  # error: [type-assertion-failure]
+
+# This function might seem a bit silly, but it's a pattern that exists in real-world code!
+# see https://github.com/bokeh/bokeh/blob/adef0157284696ce86961b2089c75fddda53c15c/src/bokeh/core/property/container.py#L130-L140
+def no_invalid_return_diagnostic_here_either[T](x: A[T]) -> ASub[T]:
+    if isinstance(x, A):
+        if isinstance(x, ASub):
+            return x
+        else:
+            return ASub()
+    else:
+        # We *would* emit a diagnostic here complaining that it's an invalid `return` statement
+        # ...except that we (correctly) infer that this branch is unreachable, so the complaint
+        # is null and void (and therefore we don't emit a diagnostic)
+        return x
+```
diff --git a/crates/ty_python_semantic/src/types/function.rs b/crates/ty_python_semantic/src/types/function.rs
index 2b284830c9..2c13e03083 100644
--- a/crates/ty_python_semantic/src/types/function.rs
+++ b/crates/ty_python_semantic/src/types/function.rs
@@ -76,9 +76,9 @@ use crate::types::narrow::ClassInfoConstraintFunction;
 use crate::types::signatures::{CallableSignature, Signature};
 use crate::types::visitor::any_over_type;
 use crate::types::{
-    BoundMethodType, CallableType, ClassLiteral, ClassType, DeprecatedInstance, DynamicType,
-    KnownClass, Truthiness, Type, TypeMapping, TypeRelation, TypeTransformer, TypeVarInstance,
-    UnionBuilder, all_members, walk_type_mapping,
+    BoundMethodType, CallableType, ClassBase, ClassLiteral, ClassType, DeprecatedInstance,
+    DynamicType, KnownClass, Truthiness, Type, TypeMapping, TypeRelation, TypeTransformer,
+    TypeVarInstance, UnionBuilder, all_members, walk_type_mapping,
 };
 use crate::{Db, FxOrderSet, ModuleName, resolve_module};
 
@@ -901,7 +901,12 @@ fn is_instance_truthiness<'db>(
         if let Type::NominalInstance(instance) = ty {
             if instance
                 .class
-                .is_subclass_of(db, ClassType::NonGeneric(class))
+                .iter_mro(db)
+                .filter_map(ClassBase::into_class)
+                .any(|c| match c {
+                    ClassType::Generic(c) => c.origin(db) == class,
+                    ClassType::NonGeneric(c) => c == class,
+                })
             {
                 return true;
             }