diff --git a/src/compiler/checker.ts b/src/compiler/checker.ts
index 4c1ad31d43ff6..31cf2e1acebf1 100644
--- a/src/compiler/checker.ts
+++ b/src/compiler/checker.ts
@@ -20893,6 +20893,11 @@ export function createTypeChecker(host: TypeCheckerHost): TypeChecker {
                     // Relate components directly before falling back to constraint relationships
                     // A type S[K] is related to a type T[J] if S is related to T and K is related to J.
                     if (result = isRelatedTo((source as IndexedAccessType).objectType, (target as IndexedAccessType).objectType, RecursionFlags.Both, reportErrors)) {
+                        // This does _not_ generalize - specific instantiations of `S[K]` and `T[J]` may be related, even if the indexed accesses generally are not.
+                        // For example, `S = {x: string, a: string}`, `T = {x: string, b: string}`, `K = J = "x"`. `S` and `T` are unrelated, but the result of executing
+                        // `S["x"]` and `T["x"]` _are_. Given that, we have to flag the object type comparison here as "unreliable", since while the generic result can reliably
+                        // be used in the affirmative case, it failing is not an indicator that the structural result will not succeed.
+                        instantiateType((source as IndexedAccessType).objectType, reportUnreliableMapper);
                         result &= isRelatedTo((source as IndexedAccessType).indexType, (target as IndexedAccessType).indexType, RecursionFlags.Both, reportErrors);
                     }
                     if (result) {
diff --git a/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.js b/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.js
new file mode 100644
index 0000000000000..f8daca1c7f6ca
--- /dev/null
+++ b/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.js
@@ -0,0 +1,45 @@
+//// [genericIndexedAccessVarianceComparisonResultCorrect.ts]
+class A {
+    x: string = 'A';
+    y: number = 0;
+}
+
+class B {
+    x: string = 'B';
+    z: boolean = true;
+}
+
+type T<X extends { x: any }> = Pick<X, 'x'>;
+
+type C = T<A>;
+type D = T<B>;
+
+type C_extends_D = C extends D ? true : false;                                  // true
+type PickA_extends_PickB = Pick<A, 'x'> extends Pick<B, 'x'> ? true : false;    // true
+type TA_extends_TB = T<A> extends T<B> ? true : false;                          // should be true
+
+declare let a: T<A>;
+declare let b: T<B>;
+declare let c: C;
+declare let d: D;
+
+b = a;      // should be no error
+c = d;
+
+//// [genericIndexedAccessVarianceComparisonResultCorrect.js]
+var A = /** @class */ (function () {
+    function A() {
+        this.x = 'A';
+        this.y = 0;
+    }
+    return A;
+}());
+var B = /** @class */ (function () {
+    function B() {
+        this.x = 'B';
+        this.z = true;
+    }
+    return B;
+}());
+b = a; // should be no error
+c = d;
diff --git a/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.symbols b/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.symbols
new file mode 100644
index 0000000000000..5636f82258090
--- /dev/null
+++ b/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.symbols
@@ -0,0 +1,83 @@
+=== tests/cases/compiler/genericIndexedAccessVarianceComparisonResultCorrect.ts ===
+class A {
+>A : Symbol(A, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 0, 0))
+
+    x: string = 'A';
+>x : Symbol(A.x, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 0, 9))
+
+    y: number = 0;
+>y : Symbol(A.y, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 1, 20))
+}
+
+class B {
+>B : Symbol(B, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 3, 1))
+
+    x: string = 'B';
+>x : Symbol(B.x, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 5, 9))
+
+    z: boolean = true;
+>z : Symbol(B.z, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 6, 20))
+}
+
+type T<X extends { x: any }> = Pick<X, 'x'>;
+>T : Symbol(T, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 8, 1))
+>X : Symbol(X, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 10, 7))
+>x : Symbol(x, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 10, 18))
+>Pick : Symbol(Pick, Decl(lib.es5.d.ts, --, --))
+>X : Symbol(X, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 10, 7))
+
+type C = T<A>;
+>C : Symbol(C, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 10, 44))
+>T : Symbol(T, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 8, 1))
+>A : Symbol(A, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 0, 0))
+
+type D = T<B>;
+>D : Symbol(D, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 12, 14))
+>T : Symbol(T, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 8, 1))
+>B : Symbol(B, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 3, 1))
+
+type C_extends_D = C extends D ? true : false;                                  // true
+>C_extends_D : Symbol(C_extends_D, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 13, 14))
+>C : Symbol(C, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 10, 44))
+>D : Symbol(D, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 12, 14))
+
+type PickA_extends_PickB = Pick<A, 'x'> extends Pick<B, 'x'> ? true : false;    // true
+>PickA_extends_PickB : Symbol(PickA_extends_PickB, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 15, 46))
+>Pick : Symbol(Pick, Decl(lib.es5.d.ts, --, --))
+>A : Symbol(A, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 0, 0))
+>Pick : Symbol(Pick, Decl(lib.es5.d.ts, --, --))
+>B : Symbol(B, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 3, 1))
+
+type TA_extends_TB = T<A> extends T<B> ? true : false;                          // should be true
+>TA_extends_TB : Symbol(TA_extends_TB, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 16, 76))
+>T : Symbol(T, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 8, 1))
+>A : Symbol(A, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 0, 0))
+>T : Symbol(T, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 8, 1))
+>B : Symbol(B, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 3, 1))
+
+declare let a: T<A>;
+>a : Symbol(a, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 19, 11))
+>T : Symbol(T, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 8, 1))
+>A : Symbol(A, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 0, 0))
+
+declare let b: T<B>;
+>b : Symbol(b, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 20, 11))
+>T : Symbol(T, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 8, 1))
+>B : Symbol(B, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 3, 1))
+
+declare let c: C;
+>c : Symbol(c, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 21, 11))
+>C : Symbol(C, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 10, 44))
+
+declare let d: D;
+>d : Symbol(d, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 22, 11))
+>D : Symbol(D, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 12, 14))
+
+b = a;      // should be no error
+>b : Symbol(b, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 20, 11))
+>a : Symbol(a, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 19, 11))
+
+c = d;
+>c : Symbol(c, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 21, 11))
+>d : Symbol(d, Decl(genericIndexedAccessVarianceComparisonResultCorrect.ts, 22, 11))
+
diff --git a/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.types b/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.types
new file mode 100644
index 0000000000000..e04f48ba89210
--- /dev/null
+++ b/tests/baselines/reference/genericIndexedAccessVarianceComparisonResultCorrect.types
@@ -0,0 +1,72 @@
+=== tests/cases/compiler/genericIndexedAccessVarianceComparisonResultCorrect.ts ===
+class A {
+>A : A
+
+    x: string = 'A';
+>x : string
+>'A' : "A"
+
+    y: number = 0;
+>y : number
+>0 : 0
+}
+
+class B {
+>B : B
+
+    x: string = 'B';
+>x : string
+>'B' : "B"
+
+    z: boolean = true;
+>z : boolean
+>true : true
+}
+
+type T<X extends { x: any }> = Pick<X, 'x'>;
+>T : T<X>
+>x : any
+
+type C = T<A>;
+>C : { x: string; }
+
+type D = T<B>;
+>D : { x: string; }
+
+type C_extends_D = C extends D ? true : false;                                  // true
+>C_extends_D : true
+>true : true
+>false : false
+
+type PickA_extends_PickB = Pick<A, 'x'> extends Pick<B, 'x'> ? true : false;    // true
+>PickA_extends_PickB : true
+>true : true
+>false : false
+
+type TA_extends_TB = T<A> extends T<B> ? true : false;                          // should be true
+>TA_extends_TB : true
+>true : true
+>false : false
+
+declare let a: T<A>;
+>a : T<A>
+
+declare let b: T<B>;
+>b : T<B>
+
+declare let c: C;
+>c : C
+
+declare let d: D;
+>d : D
+
+b = a;      // should be no error
+>b = a : T<A>
+>b : T<B>
+>a : T<A>
+
+c = d;
+>c = d : D
+>c : C
+>d : D
+
diff --git a/tests/cases/compiler/genericIndexedAccessVarianceComparisonResultCorrect.ts b/tests/cases/compiler/genericIndexedAccessVarianceComparisonResultCorrect.ts
new file mode 100644
index 0000000000000..b0b3f2dd311ba
--- /dev/null
+++ b/tests/cases/compiler/genericIndexedAccessVarianceComparisonResultCorrect.ts
@@ -0,0 +1,26 @@
+class A {
+    x: string = 'A';
+    y: number = 0;
+}
+
+class B {
+    x: string = 'B';
+    z: boolean = true;
+}
+
+type T<X extends { x: any }> = Pick<X, 'x'>;
+
+type C = T<A>;
+type D = T<B>;
+
+type C_extends_D = C extends D ? true : false;                                  // true
+type PickA_extends_PickB = Pick<A, 'x'> extends Pick<B, 'x'> ? true : false;    // true
+type TA_extends_TB = T<A> extends T<B> ? true : false;                          // should be true
+
+declare let a: T<A>;
+declare let b: T<B>;
+declare let c: C;
+declare let d: D;
+
+b = a;      // should be no error
+c = d;
\ No newline at end of file