diff --git a/include/nanobind/nb_class.h b/include/nanobind/nb_class.h
index 4120f43f..ec4bc013 100644
--- a/include/nanobind/nb_class.h
+++ b/include/nanobind/nb_class.h
@@ -340,6 +340,16 @@ class class_ : public object {
         sizeof...(Ts) == !std::is_same_v<Base, T> + !std::is_same_v<Alias, T>,
         "nanobind::class_<> was invoked with extra arguments that could not be handled");
 
+    // Fail on virtual bases -- they need a this-ptr adjustment, but they're
+    // not amenable to the runtime test in the class_ constructor (because
+    // a C-style cast will do reinterpret_cast if static_cast is invalid).
+    // Primary but inaccessible (ambiguous or private) bases will also
+    // fail is_accessible_static_base_of; the !is_convertible option is to
+    // avoid mis-detecting them as virtual bases.
+    static_assert(!std::is_convertible_v<T*, Base*> ||
+                  detail::is_accessible_static_base_of<Base, T>::value,
+                  "nanobind does not support virtual base classes");
+
     template <typename... Extra>
     NB_INLINE class_(handle scope, const char *name, const Extra &... extra) {
         detail::type_init_data d;
@@ -354,6 +364,13 @@ class class_ : public object {
         if constexpr (!std::is_same_v<Base, T>) {
             d.base = &typeid(Base);
             d.flags |= (uint32_t) detail::type_init_flags::has_base;
+
+            if (uintptr_t offset = (uintptr_t) (Base*) (T*) 0x1000 - 0x1000) {
+                detail::raise("nanobind::class_<>: base class %s is at offset "
+                              "%td within %s! nanobind does not support "
+                              "multiple inheritance", typeid(Base).name(),
+                              offset, typeid(T).name());
+            }
         }
 
         if constexpr (!std::is_same_v<Alias, T>)
diff --git a/include/nanobind/nb_traits.h b/include/nanobind/nb_traits.h
index 66ea2105..83601d3f 100644
--- a/include/nanobind/nb_traits.h
+++ b/include/nanobind/nb_traits.h
@@ -132,6 +132,14 @@ struct detector<std::void_t<Op<Arg>>, Op, Arg>
    avoid redundancy when combined with nb::arg(...).none(). */
 template <typename T> struct remove_opt_mono { using type = T; };
 
+template <typename Base, typename Derived>
+struct is_accessible_static_base_of {
+    template <typename B = Base, typename D = Derived>
+    static decltype(static_cast<D*>(std::declval<B*>()), std::true_type()) check(B*);
+    static std::false_type check(...);
+    static constexpr bool value = decltype(check((Base*)nullptr))::value;
+};
+
 NAMESPACE_END(detail)
 
 template <typename... Args>
diff --git a/tests/test_classes.cpp b/tests/test_classes.cpp
index e54e8261..adcd7c19 100644
--- a/tests/test_classes.cpp
+++ b/tests/test_classes.cpp
@@ -477,4 +477,23 @@ NB_MODULE(test_classes_ext, m) {
     m.def("polymorphic_factory_2", []() { return (PolymorphicBase *) new AnotherPolymorphicSubclass(); });
     m.def("factory", []() { return (Base *) new Subclass(); });
     m.def("factory_2", []() { return (Base *) new AnotherSubclass(); });
+
+    // Test detection of unsupported base/derived relationships
+    // (nanobind requires base subobjects to be at offset zero in the
+    // derived class)
+    struct DerivedBecomesPolymorphic : Struct {
+        virtual ~DerivedBecomesPolymorphic() {}
+    };
+    struct DerivedNonPrimary : Big, Struct {};
+    struct DerivedVirt : virtual Struct {};
+    m.def("bind_newly_polymorphic_subclass", []() {
+        nb::class_<DerivedBecomesPolymorphic, Struct>(
+            nb::handle(), "DerivedBecomesPolymorphic");
+    });
+    m.def("bind_subclass_with_non_primary_base", []() {
+        nb::class_<DerivedNonPrimary, Struct>(nb::handle(), "DerivedNonPrimary");
+    });
+    static_assert(!nb::detail::is_accessible_static_base_of<Struct, DerivedVirt>::value);
+    // this fails at compile time:
+    //nb::class_<DerivedVirt, Struct>(nb::handle(), "DerivedVirt");
 }
diff --git a/tests/test_classes.py b/tests/test_classes.py
index 6fc27ca8..d4305e14 100644
--- a/tests/test_classes.py
+++ b/tests/test_classes.py
@@ -631,3 +631,10 @@ def name(self):
             assert t.go(d2) == 'Rufus says woof'
         finally:
             t.Dog.name = old
+
+
+def test35_non_primary():
+    with pytest.raises(RuntimeError, match="not support multiple inheritance"):
+        t.bind_newly_polymorphic_subclass()
+    with pytest.raises(RuntimeError, match="not support multiple inheritance"):
+        t.bind_subclass_with_non_primary_base()