diff --git a/mypy/checkexpr.py b/mypy/checkexpr.py
index 44855f49afaf..04035c07c4c1 100644
--- a/mypy/checkexpr.py
+++ b/mypy/checkexpr.py
@@ -6040,7 +6040,15 @@ def check_for_comp(self, e: GeneratorExpr | DictionaryComprehension) -> None:
 
                 # values are only part of the comprehension when all conditions are true
                 true_map, false_map = self.chk.find_isinstance_check(condition)
-                self.chk.push_type_map(true_map)
+                if mypy.checker.is_unreachable_map(true_map):
+                    # The condition can never be true. Unlike statements, the
+                    # left expression is still type checked, so apply the
+                    # impossible narrowing to the binder instead of marking
+                    # the frame unreachable, which would discard it (#21635).
+                    for expr, typ in true_map.items():
+                        self.chk.binder.put(expr, typ)
+                else:
+                    self.chk.push_type_map(true_map)
 
                 if codes.REDUNDANT_EXPR in self.chk.options.enabled_error_codes:
                     if mypy.checker.is_unreachable_map(true_map):
diff --git a/test-data/unit/check-isinstance.test b/test-data/unit/check-isinstance.test
index acd81839fcdc..c0ae4db3eddd 100644
--- a/test-data/unit/check-isinstance.test
+++ b/test-data/unit/check-isinstance.test
@@ -1614,6 +1614,37 @@ reveal_type(g) # N: Revealed type is "typing.Generator[builtins.int, None, None]
 reveal_type(d) # N: Revealed type is "builtins.dict[builtins.int, builtins.int]"
 [builtins fixtures/isinstancelist.pyi]
 
+[case testComprehensionIsInstanceImpossibleIntersection]
+# https://github.com/python/mypy/issues/21635
+from typing import List
+
+class X:
+    def f(self) -> int:
+        return 0
+class Y:
+    def f(self) -> str:
+        return ''
+
+xs: List[X] = []
+l: List[Y] = [x for x in xs if isinstance(x, Y)]
+g = (reveal_type(x) for x in xs if isinstance(x, Y))  # N: Revealed type is "Never"
+d = {0: x for x in xs if isinstance(x, Y)}
+reveal_type(d)  # N: Revealed type is "builtins.dict[builtins.int, Never]"
+[builtins fixtures/isinstancelist.pyi]
+
+[case testComprehensionIsSubclassImpossibleIntersectionFinal]
+# https://github.com/python/mypy/issues/21635
+from typing import List, Type
+from typing_extensions import final
+
+@final
+class F: ...
+class Other: ...
+
+os: List[Other] = []
+fs: List[F] = [o for o in os if isinstance(o, F)]
+[builtins fixtures/isinstancelist.pyi]
+
 [case testIsinstanceInWrongOrderInBooleanOp]
 # flags: --warn-unreachable
 class A: