diff --git a/crates/ty_python_semantic/resources/mdtest/type_properties/is_disjoint_from.md b/crates/ty_python_semantic/resources/mdtest/type_properties/is_disjoint_from.md
index 166d67edd0..02f50cc412 100644
--- a/crates/ty_python_semantic/resources/mdtest/type_properties/is_disjoint_from.md
+++ b/crates/ty_python_semantic/resources/mdtest/type_properties/is_disjoint_from.md
@@ -95,7 +95,7 @@ python-version = "3.12"
 ```
 
 ```py
-from typing import final
+from typing import Any, final
 from ty_extensions import static_assert, is_disjoint_from
 
 @final
@@ -106,9 +106,12 @@ class Foo[T]:
 class A: ...
 class B: ...
 
+static_assert(not is_disjoint_from(A, B))
 static_assert(not is_disjoint_from(Foo[A], Foo[B]))
+static_assert(not is_disjoint_from(Foo[A], Foo[Any]))
+static_assert(not is_disjoint_from(Foo[Any], Foo[B]))
 
-# TODO: `int` and `str` are disjoint bases, so these should be disjoint.
+# `Foo[Never]` is a subtype of both `Foo[int]` and `Foo[str]`.
 static_assert(not is_disjoint_from(Foo[int], Foo[str]))
 ```
 
diff --git a/crates/ty_python_semantic/src/types/class.rs b/crates/ty_python_semantic/src/types/class.rs
index a5122431dd..492ed63f21 100644
--- a/crates/ty_python_semantic/src/types/class.rs
+++ b/crates/ty_python_semantic/src/types/class.rs
@@ -718,6 +718,31 @@ impl<'db> ClassType<'db> {
             .find_map(|base| base.as_disjoint_base(db))
     }
 
+    /// Return `true` if this class could exist in the MRO of `other`.
+    pub(super) fn could_exist_in_mro_of(self, db: &'db dyn Db, other: Self) -> bool {
+        other
+            .iter_mro(db)
+            .filter_map(ClassBase::into_class)
+            .any(|class| match (self, class) {
+                (ClassType::NonGeneric(this_class), ClassType::NonGeneric(other_class)) => {
+                    this_class == other_class
+                }
+                (ClassType::Generic(this_alias), ClassType::Generic(other_alias)) => {
+                    this_alias.origin(db) == other_alias.origin(db)
+                        && !this_alias
+                            .specialization(db)
+                            .is_disjoint_from(
+                                db,
+                                other_alias.specialization(db),
+                                InferableTypeVars::None,
+                            )
+                            .is_always_satisfied(db)
+                }
+                (ClassType::NonGeneric(_), ClassType::Generic(_))
+                | (ClassType::Generic(_), ClassType::NonGeneric(_)) => false,
+            })
+    }
+
     /// Return `true` if this class could coexist in an MRO with `other`.
     ///
     /// For two given classes `A` and `B`, it is often possible to say for sure
@@ -729,16 +754,11 @@ impl<'db> ClassType<'db> {
         }
 
         if self.is_final(db) {
-            return self
-                .iter_mro(db)
-                .filter_map(ClassBase::into_class)
-                .any(|class| class.class_literal(db).0 == other.class_literal(db).0);
+            return other.could_exist_in_mro_of(db, self);
         }
+
         if other.is_final(db) {
-            return other
-                .iter_mro(db)
-                .filter_map(ClassBase::into_class)
-                .any(|class| class.class_literal(db).0 == self.class_literal(db).0);
+            return self.could_exist_in_mro_of(db, other);
         }
 
         // Two disjoint bases can only coexist in an MRO if one is a subclass of the other.
diff --git a/crates/ty_python_semantic/src/types/generics.rs b/crates/ty_python_semantic/src/types/generics.rs
index ade46d77ca..58ccd28ca0 100644
--- a/crates/ty_python_semantic/src/types/generics.rs
+++ b/crates/ty_python_semantic/src/types/generics.rs
@@ -11,7 +11,7 @@ use crate::semantic_index::scope::{FileScopeId, NodeWithScopeKind, ScopeId};
 use crate::semantic_index::{SemanticIndex, semantic_index};
 use crate::types::class::ClassType;
 use crate::types::class_base::ClassBase;
-use crate::types::constraints::ConstraintSet;
+use crate::types::constraints::{ConstraintSet, IteratorConstraintsExtension};
 use crate::types::instance::{Protocol, ProtocolInstanceType};
 use crate::types::signatures::{Parameters, ParametersKind};
 use crate::types::tuple::{TupleSpec, TupleType, walk_tuple_type};
@@ -1226,18 +1226,20 @@ impl<'db> Specialization<'db> {
         let self_materialization_kind = self.materialization_kind(db);
         let other_materialization_kind = other.materialization_kind(db);
 
-        let mut result = ConstraintSet::from(true);
-        for ((bound_typevar, self_type), other_type) in (generic_context.variables(db))
-            .zip(self.types(db))
-            .zip(other.types(db))
-        {
+        let types = itertools::izip!(
+            generic_context.variables(db),
+            self.types(db),
+            other.types(db)
+        );
+
+        types.when_all(db, |(bound_typevar, self_type, other_type)| {
             // Subtyping/assignability of each type in the specialization depends on the variance
             // of the corresponding typevar:
             //   - covariant: verify that self_type <: other_type
             //   - contravariant: verify that other_type <: self_type
             //   - invariant: verify that self_type <: other_type AND other_type <: self_type
             //   - bivariant: skip, can't make subtyping/assignability false
-            let compatible = match bound_typevar.variance(db) {
+            match bound_typevar.variance(db) {
                 TypeVarVariance::Invariant => has_relation_in_invariant_position(
                     db,
                     self_type,
@@ -1266,13 +1268,82 @@ impl<'db> Specialization<'db> {
                     disjointness_visitor,
                 ),
                 TypeVarVariance::Bivariant => ConstraintSet::from(true),
-            };
-            if result.intersect(db, compatible).is_never_satisfied(db) {
-                return result;
             }
+        })
+    }
+
+    pub(crate) fn is_disjoint_from(
+        self,
+        db: &'db dyn Db,
+        other: Self,
+        inferable: InferableTypeVars<'_, 'db>,
+    ) -> ConstraintSet<'db> {
+        self.is_disjoint_from_impl(
+            db,
+            other,
+            inferable,
+            &IsDisjointVisitor::default(),
+            &HasRelationToVisitor::default(),
+        )
+    }
+
+    pub(crate) fn is_disjoint_from_impl(
+        self,
+        db: &'db dyn Db,
+        other: Self,
+        inferable: InferableTypeVars<'_, 'db>,
+        disjointness_visitor: &IsDisjointVisitor<'db>,
+        relation_visitor: &HasRelationToVisitor<'db>,
+    ) -> ConstraintSet<'db> {
+        let generic_context = self.generic_context(db);
+        if generic_context != other.generic_context(db) {
+            return ConstraintSet::from(true);
         }
 
-        result
+        if let (Some(self_tuple), Some(other_tuple)) = (self.tuple_inner(db), other.tuple_inner(db))
+        {
+            return self_tuple.is_disjoint_from_impl(
+                db,
+                other_tuple,
+                inferable,
+                disjointness_visitor,
+                relation_visitor,
+            );
+        }
+
+        let types = itertools::izip!(
+            generic_context.variables(db),
+            self.types(db),
+            other.types(db)
+        );
+
+        types.when_all(
+            db,
+            |(bound_typevar, self_type, other_type)| match bound_typevar.variance(db) {
+                // TODO: This check can lead to false negatives.
+                //
+                // For example, `Foo[int]` and `Foo[bool]` are disjoint, even though `bool` is a subtype
+                // of `int`. However, given two non-inferable type variables `T` and `U`, `Foo[T]` and
+                // `Foo[U]` should not be considered disjoint, as `T` and `U` could be specialized to the
+                // same type. We don't currently have a good typing relationship to represent this.
+                TypeVarVariance::Invariant => self_type.is_disjoint_from_impl(
+                    db,
+                    *other_type,
+                    inferable,
+                    disjointness_visitor,
+                    relation_visitor,
+                ),
+
+                // If `Foo[T]` is covariant in `T`, `Foo[Never]` is a subtype of `Foo[A]` and `Foo[B]`
+                TypeVarVariance::Covariant => ConstraintSet::from(false),
+
+                // If `Foo[T]` is contravariant in `T`, `Foo[A | B]` is a subtype of `Foo[A]` and `Foo[B]`
+                TypeVarVariance::Contravariant => ConstraintSet::from(false),
+
+                // If `Foo[T]` is bivariant in `T`, `Foo[A]` and `Foo[B]` are mutual subtypes.
+                TypeVarVariance::Bivariant => ConstraintSet::from(false),
+            },
+        )
     }
 
     pub(crate) fn is_equivalent_to_impl(
diff --git a/crates/ty_python_semantic/src/types/tuple.rs b/crates/ty_python_semantic/src/types/tuple.rs
index 9b046cd4cf..f0cc3bedc8 100644
--- a/crates/ty_python_semantic/src/types/tuple.rs
+++ b/crates/ty_python_semantic/src/types/tuple.rs
@@ -288,6 +288,23 @@ impl<'db> TupleType<'db> {
         )
     }
 
+    pub(crate) fn is_disjoint_from_impl(
+        self,
+        db: &'db dyn Db,
+        other: Self,
+        inferable: InferableTypeVars<'_, 'db>,
+        disjointness_visitor: &IsDisjointVisitor<'db>,
+        relation_visitor: &HasRelationToVisitor<'db>,
+    ) -> ConstraintSet<'db> {
+        self.tuple(db).is_disjoint_from_impl(
+            db,
+            other.tuple(db),
+            inferable,
+            disjointness_visitor,
+            relation_visitor,
+        )
+    }
+
     pub(crate) fn is_equivalent_to_impl(
         self,
         db: &'db dyn Db,