diff --git a/src/compiler/checker.ts b/src/compiler/checker.ts
index 58d6a8b867e20..9084995db80cf 100644
--- a/src/compiler/checker.ts
+++ b/src/compiler/checker.ts
@@ -15276,7 +15276,7 @@ export function createTypeChecker(host: TypeCheckerHost): TypeChecker {
         return undefined;
     }
 
-    function getSignatureInstantiation(signature: Signature, typeArguments: Type[] | undefined, isJavascript: boolean, inferredTypeParameters?: readonly TypeParameter[]): Signature {
+    function getSignatureInstantiation(signature: Signature, typeArguments: readonly Type[] | undefined, isJavascript: boolean, inferredTypeParameters?: readonly TypeParameter[]): Signature {
         const instantiatedSignature = getSignatureInstantiationWithoutFillingInTypeArguments(signature, fillMissingTypeArguments(typeArguments, signature.typeParameters, getMinTypeArgumentCount(signature.typeParameters), isJavascript));
         if (inferredTypeParameters) {
             const returnSignature = getSingleCallOrConstructSignature(getReturnTypeOfSignature(instantiatedSignature));
@@ -22963,10 +22963,15 @@ export function createTypeChecker(host: TypeCheckerHost): TypeChecker {
             ) {
                 // We have instantiations of the same anonymous type (which typically will be the type of a
                 // method). Simply do a pairwise comparison of the signatures in the two signature lists instead
-                // of the much more expensive N * M comparison matrix we explore below. We erase type parameters
-                // as they are known to always be the same.
+                // of the much more expensive N * M comparison matrix we explore below. We instantiate the source
+                // signature with the type parameters of the target signature to unify the two.
                 for (let i = 0; i < targetSignatures.length; i++) {
-                    const related = signatureRelatedTo(sourceSignatures[i], targetSignatures[i], /*erase*/ true, reportErrors, intersectionState, incompatibleReporter(sourceSignatures[i], targetSignatures[i]));
+                    const sourceSignature = sourceSignatures[i];
+                    const targetSignature = targetSignatures[i];
+                    const instantiatedSourceSignature = targetSignature.typeParameters ?
+                        getSignatureInstantiation(sourceSignature, targetSignature.typeParameters, isInJSFile(sourceSignature.declaration)) :
+                        sourceSignature;
+                    const related = signatureRelatedTo(instantiatedSourceSignature, targetSignature, /*erase*/ false, reportErrors, intersectionState, incompatibleReporter(instantiatedSourceSignature, targetSignature));
                     if (!related) {
                         return Ternary.False;
                     }
diff --git a/tests/baselines/reference/complexRecursiveCollections.types b/tests/baselines/reference/complexRecursiveCollections.types
index 0aa394d46b370..2a6a5c12d81a7 100644
--- a/tests/baselines/reference/complexRecursiveCollections.types
+++ b/tests/baselines/reference/complexRecursiveCollections.types
@@ -1139,7 +1139,7 @@ declare module Immutable {
 >Seq : typeof Seq
 
     function isSeq(maybeSeq: any): maybeSeq is Seq.Indexed<any> | Seq.Keyed<any, any>;
->isSeq : (maybeSeq: any) => maybeSeq is Indexed<any> | Keyed<any, any>
+>isSeq : (maybeSeq: any) => maybeSeq is Keyed<any, any> | Indexed<any>
 >maybeSeq : any
 >Seq : any
 >Seq : any
diff --git a/tests/baselines/reference/genericSignatureRelations.js b/tests/baselines/reference/genericSignatureRelations.js
new file mode 100644
index 0000000000000..48b363df00765
--- /dev/null
+++ b/tests/baselines/reference/genericSignatureRelations.js
@@ -0,0 +1,25 @@
+//// [tests/cases/compiler/genericSignatureRelations.ts] ////
+
+//// [genericSignatureRelations.ts]
+// Repro from #48070
+
+type S<X> = <T>() => T extends X ? 1 : '2';
+
+type Foo1 = S<'s1'>;
+type Foo2 = S<'s2'>;
+
+type Result1 = Foo1 extends Foo2 ? true : false;
+type Result2 = S<'s1'> extends S<'s2'> ? true : false;
+
+
+//// [genericSignatureRelations.js]
+"use strict";
+// Repro from #48070
+
+
+//// [genericSignatureRelations.d.ts]
+type S<X> = <T>() => T extends X ? 1 : '2';
+type Foo1 = S<'s1'>;
+type Foo2 = S<'s2'>;
+type Result1 = Foo1 extends Foo2 ? true : false;
+type Result2 = S<'s1'> extends S<'s2'> ? true : false;
diff --git a/tests/baselines/reference/genericSignatureRelations.symbols b/tests/baselines/reference/genericSignatureRelations.symbols
new file mode 100644
index 0000000000000..13a4c1233afbc
--- /dev/null
+++ b/tests/baselines/reference/genericSignatureRelations.symbols
@@ -0,0 +1,30 @@
+//// [tests/cases/compiler/genericSignatureRelations.ts] ////
+
+=== genericSignatureRelations.ts ===
+// Repro from #48070
+
+type S<X> = <T>() => T extends X ? 1 : '2';
+>S : Symbol(S, Decl(genericSignatureRelations.ts, 0, 0))
+>X : Symbol(X, Decl(genericSignatureRelations.ts, 2, 7))
+>T : Symbol(T, Decl(genericSignatureRelations.ts, 2, 13))
+>T : Symbol(T, Decl(genericSignatureRelations.ts, 2, 13))
+>X : Symbol(X, Decl(genericSignatureRelations.ts, 2, 7))
+
+type Foo1 = S<'s1'>;
+>Foo1 : Symbol(Foo1, Decl(genericSignatureRelations.ts, 2, 43))
+>S : Symbol(S, Decl(genericSignatureRelations.ts, 0, 0))
+
+type Foo2 = S<'s2'>;
+>Foo2 : Symbol(Foo2, Decl(genericSignatureRelations.ts, 4, 20))
+>S : Symbol(S, Decl(genericSignatureRelations.ts, 0, 0))
+
+type Result1 = Foo1 extends Foo2 ? true : false;
+>Result1 : Symbol(Result1, Decl(genericSignatureRelations.ts, 5, 20))
+>Foo1 : Symbol(Foo1, Decl(genericSignatureRelations.ts, 2, 43))
+>Foo2 : Symbol(Foo2, Decl(genericSignatureRelations.ts, 4, 20))
+
+type Result2 = S<'s1'> extends S<'s2'> ? true : false;
+>Result2 : Symbol(Result2, Decl(genericSignatureRelations.ts, 7, 48))
+>S : Symbol(S, Decl(genericSignatureRelations.ts, 0, 0))
+>S : Symbol(S, Decl(genericSignatureRelations.ts, 0, 0))
+
diff --git a/tests/baselines/reference/genericSignatureRelations.types b/tests/baselines/reference/genericSignatureRelations.types
new file mode 100644
index 0000000000000..b923d1a246610
--- /dev/null
+++ b/tests/baselines/reference/genericSignatureRelations.types
@@ -0,0 +1,24 @@
+//// [tests/cases/compiler/genericSignatureRelations.ts] ////
+
+=== genericSignatureRelations.ts ===
+// Repro from #48070
+
+type S<X> = <T>() => T extends X ? 1 : '2';
+>S : S<X>
+
+type Foo1 = S<'s1'>;
+>Foo1 : <T>() => T extends "s1" ? 1 : "2"
+
+type Foo2 = S<'s2'>;
+>Foo2 : <T>() => T extends "s2" ? 1 : "2"
+
+type Result1 = Foo1 extends Foo2 ? true : false;
+>Result1 : false
+>true : true
+>false : false
+
+type Result2 = S<'s1'> extends S<'s2'> ? true : false;
+>Result2 : false
+>true : true
+>false : false
+
diff --git a/tests/cases/compiler/genericSignatureRelations.ts b/tests/cases/compiler/genericSignatureRelations.ts
new file mode 100644
index 0000000000000..c2e6ef3daaa6f
--- /dev/null
+++ b/tests/cases/compiler/genericSignatureRelations.ts
@@ -0,0 +1,12 @@
+// @strict: true
+// @declaration: true
+
+// Repro from #48070
+
+type S<X> = <T>() => T extends X ? 1 : '2';
+
+type Foo1 = S<'s1'>;
+type Foo2 = S<'s2'>;
+
+type Result1 = Foo1 extends Foo2 ? true : false;
+type Result2 = S<'s1'> extends S<'s2'> ? true : false;