diff --git a/mypy/build.py b/mypy/build.py
index a03a6eb8972c..96a67105c816 100644
--- a/mypy/build.py
+++ b/mypy/build.py
@@ -3482,12 +3482,16 @@ def finish_passes(self) -> None:
             # We should always patch indirect dependencies, even in full (non-incremental) builds,
             # because the cache still may be written, and it must be correct.
             self.patch_indirect_dependencies(
-                # Two possible sources of indirect dependencies:
+                # Three possible sources of indirect dependencies:
                 # * Symbols not directly imported in this module but accessed via an attribute
                 #   or via a re-export (vast majority of these recorded in semantic analysis).
                 # * For each expression type we need to record definitions of type components
                 #   since "meaning" of the type may be updated when definitions are updated.
-                self.tree.module_refs | self.type_checker().module_refs,
+                # * Additional dependencies reported by plugins (e.g. mypyc, see
+                #   MypycPlugin.get_additional_indirect_deps).
+                self.tree.module_refs
+                | self.type_checker().module_refs
+                | manager.plugin.get_additional_indirect_deps(self.tree),
                 set(self.type_map().values()),
             )
 
diff --git a/mypy/plugin.py b/mypy/plugin.py
index 383b07af87c0..d0e5add71a5b 100644
--- a/mypy/plugin.py
+++ b/mypy/plugin.py
@@ -587,6 +587,17 @@ def get_additional_deps(self, file: MypyFile) -> list[tuple[int, str, int]]:
         """
         return []
 
+    def get_additional_indirect_deps(self, file: MypyFile) -> set[str]:
+        """Customize indirect dependencies for a module.
+
+        This hook is called after the module has been type checked, so
+        analyzed information (such as class MROs) is available. The
+        returned module names are recorded as indirect dependencies:
+        a change to their interfaces will invalidate this module's
+        cache, but they are not treated as imports.
+        """
+        return set()
+
     def get_type_analyze_hook(self, fullname: str) -> Callable[[AnalyzeTypeContext], Type] | None:
         """Customize behaviour of the type analyzer for given full names.
 
@@ -846,6 +857,12 @@ def get_additional_deps(self, file: MypyFile) -> list[tuple[int, str, int]]:
             deps.extend(plugin.get_additional_deps(file))
         return deps
 
+    def get_additional_indirect_deps(self, file: MypyFile) -> set[str]:
+        deps: set[str] = set()
+        for plugin in self._plugins:
+            deps |= plugin.get_additional_indirect_deps(file)
+        return deps
+
     def get_type_analyze_hook(self, fullname: str) -> Callable[[AnalyzeTypeContext], Type] | None:
         # Micro-optimization: Inline iteration over plugins
         for plugin in self._plugins:
diff --git a/mypyc/codegen/emitmodule.py b/mypyc/codegen/emitmodule.py
index 3b320b532123..9130007e3f6e 100644
--- a/mypyc/codegen/emitmodule.py
+++ b/mypyc/codegen/emitmodule.py
@@ -23,7 +23,7 @@
 )
 from mypy.errors import CompileError
 from mypy.fscache import FileSystemCache
-from mypy.nodes import MypyFile
+from mypy.nodes import MypyFile, TypeInfo
 from mypy.options import Options
 from mypy.plugin import Plugin, ReportConfigContext
 from mypy.util import hash_digest, json_dumps
@@ -200,6 +200,28 @@ def get_additional_deps(self, file: MypyFile) -> list[tuple[int, str, int]]:
         # Report dependency on modules in the module's group
         return [(10, id, -1) for id in self.group_map.get(file.fullname, (None, []))[1]]
 
+    def get_additional_indirect_deps(self, file: MypyFile) -> set[str]:
+        """Modules defining MRO ancestors of classes defined in this module.
+
+        The generated C for a class (vtable arrays, getter/setter tables,
+        object struct) references every inherited method/attribute of every
+        ancestor, including ancestors defined in modules this module does
+        not import directly. Recording them as indirect dependencies makes
+        an ancestor's interface change re-trigger type checking (and hence
+        C regeneration) of this module. Only top-level classes are scanned:
+        mypyc rejects nested class definitions.
+        """
+        if file.fullname not in self.group_map:
+            return set()
+
+        mods: set[str] = set()
+        for sym in file.names.values():
+            node = sym.node
+            if isinstance(node, TypeInfo) and node.module_name == file.fullname:
+                for ancestor in node.mro[1:]:
+                    mods.add(ancestor.module_name)
+        return mods
+
 
 def parse_and_typecheck(
     sources: list[BuildSource],
diff --git a/mypyc/test-data/run-multimodule.test b/mypyc/test-data/run-multimodule.test
index 4cf391d312df..672a726ae985 100644
--- a/mypyc/test-data/run-multimodule.test
+++ b/mypyc/test-data/run-multimodule.test
@@ -1900,6 +1900,96 @@ def _force_recompile() -> int:
 from native import test
 test()
 
+[case testIncrementalCrossGroupInheritedMethodRemoved]
+# Regression: updating a transitive base class triggers recompilation of the
+# subclass-defining module (mypy#21742).
+import other_leaf
+
+def test() -> int:
+    c = other_leaf.Leaf()
+    return c.existing_method(5)
+
+[file other_base.py]
+class Base:
+    def existing_method(self, x: int) -> int:
+        return x + 1
+
+    def removed_method(self, x: int) -> int:
+        return x + 100
+
+[file other_base.py.2]
+class Base:
+    def existing_method(self, x: int) -> int:
+        return x + 1
+
+[file other_mid.py]
+from other_base import Base
+
+class Mid(Base):
+    def mid_method(self, x: int) -> int:
+        return x + 2
+
+[file other_leaf.py]
+from other_mid import Mid
+
+class Leaf(Mid):
+    pass
+
+[file driver.py]
+from native import test
+print(test())
+
+[out]
+6
+[out2]
+6
+
+[case testIncrementalCrossGroupInheritedMethodRemovedNonEmptyLeaf]
+# Regression: updating a transitive base class triggers recompilation of the
+# module defining a subclass with a non-empty body (mypy#21742).
+import other_leaf
+
+def test() -> int:
+    return other_leaf.Leaf().existing_method(5)
+
+[file other_base.py]
+class Base:
+    def existing_method(self, x: int) -> int:
+        return x + 1
+
+    def removed_method(self, x: int) -> int:
+        return x + 100
+
+[file other_base.py.2]
+class Base:
+    def existing_method(self, x: int) -> int:
+        return x + 1
+
+[file other_mid.py]
+from other_base import Base
+
+class Mid(Base):
+    def mid_method(self, x: int) -> int:
+        return x + 2
+
+[file other_leaf.py]
+from other_mid import Mid
+
+class Leaf(Mid):
+    FLAG = True
+
+    def foo(self) -> str:
+        return "foo"
+
+[file driver.py]
+from native import test
+print(test())
+
+[out]
+6
+[out2]
+6
+
 [case testCrossModuleInheritedAttrDefaultsSameGroup]
 # separate: [(["native.py"], "grp1"), (["other_a.py", "other_b.py"], "grp2")]
 # Regression: with the subclass (other_a) and base (other_b) in the same