diff --git a/mypyc/irbuild/expression.py b/mypyc/irbuild/expression.py
index e8d22a051cc4..f953dd3825ef 100644
--- a/mypyc/irbuild/expression.py
+++ b/mypyc/irbuild/expression.py
@@ -93,9 +93,12 @@
     is_list_rprimitive,
     is_none_rprimitive,
     is_object_rprimitive,
+    is_str_rprimitive,
+    is_tagged,
     is_tuple_rprimitive,
     object_rprimitive,
     set_rprimitive,
+    short_int_rprimitive,
     vec_api_by_item_type,
 )
 from mypyc.irbuild.ast_helpers import is_borrow_friendly_expr, process_conditional
@@ -119,6 +122,7 @@
     apply_dunder_specialization,
     apply_function_specialization,
     apply_method_specialization,
+    translate_getitem_with_bounds_check,
     translate_object_new,
     translate_object_setattr,
 )
@@ -137,7 +141,12 @@
 from mypyc.primitives.list_ops import list_append_op, list_extend_op, list_slice_op
 from mypyc.primitives.misc_ops import ellipsis_op, get_module_dict_op, new_slice_op, type_op
 from mypyc.primitives.set_ops import set_add_op, set_in_op, set_update_op
-from mypyc.primitives.str_ops import str_slice_op
+from mypyc.primitives.str_ops import (
+    str_adjust_index_op,
+    str_get_item_unsafe_as_int_op,
+    str_range_check_op,
+    str_slice_op,
+)
 from mypyc.primitives.tuple_ops import list_tuple_op, tuple_slice_op
 
 # Name and attribute references
@@ -918,6 +927,16 @@ def transform_comparison_expr(builder: IRBuilder, e: ComparisonExpr) -> Value:
             return result
 
     if len(e.operators) == 1:
+        # s[i] == 'x' / s[i] != 'x' (and the symmetric RHS) -> int compare of
+        # codepoints. Skips the per-iteration 1-char str allocation/lookup and
+        # generic str equality call.
+        if first_op in ("==", "!="):
+            result = try_specialize_str_index_compare(
+                builder, first_op, e.operands[0], e.operands[1], e.line
+            )
+            if result is not None:
+                return result
+
         # Special some common simple cases
         if first_op in ("is", "is not"):
             right_expr = e.operands[1]
@@ -960,6 +979,50 @@ def go(i: int, prev: Value) -> Value:
     return go(0, builder.accept(e.operands[0]))
 
 
+def try_specialize_str_index_compare(
+    builder: IRBuilder, op: str, lhs: Expression, rhs: Expression, line: int
+) -> Value | None:
+    """Specialize `s[i] == 'x'` / `s[i] != 'x'` (and the symmetric form with
+    operands swapped) into an int compare of codepoints.
+
+    Returns None if the pattern doesn't match: the indexed base must be str,
+    the index must be an integer, and the literal must be a 1-character str.
+    Multi-character or empty literals fall through to the generic str compare
+    (which still returns False for them, matching today's behavior).
+    """
+    # Normalize so the IndexExpr is on the left.
+    if isinstance(rhs, IndexExpr) and not isinstance(lhs, IndexExpr):
+        tmp = lhs
+        lhs, rhs = rhs, tmp
+    # Shape: s[i] {==, !=} "x" where "x" is exactly one codepoint.
+    if (
+        not isinstance(lhs, IndexExpr)
+        or not isinstance(rhs, StrExpr)
+        or len(rhs.value) != 1
+        or not is_str_rprimitive(builder.node_type(lhs.base))
+    ):
+        return None
+    index_type = builder.node_type(lhs.index)
+    if not (is_tagged(index_type) or is_fixed_width_rtype(index_type)):
+        return None
+
+    # ord(s[i]) with bounds check; raises IndexError for out-of-range indices,
+    # matching the behavior of the generic s[i] path.
+    codepoint = translate_getitem_with_bounds_check(
+        builder,
+        lhs.base,
+        [lhs.index],
+        lhs,
+        str_adjust_index_op,
+        str_range_check_op,
+        str_get_item_unsafe_as_int_op,
+    )
+    if codepoint is None:
+        return None
+    literal_cp = Integer(ord(rhs.value), short_int_rprimitive, line)
+    return builder.binary_op(codepoint, literal_cp, op, line)
+
+
 def try_specialize_in_expr(
     builder: IRBuilder, op: str, lhs: Expression, rhs: Expression, line: int
 ) -> Value | None:
diff --git a/mypyc/test-data/irbuild-str.test b/mypyc/test-data/irbuild-str.test
index 81cd5bd34c04..b16057f645ba 100644
--- a/mypyc/test-data/irbuild-str.test
+++ b/mypyc/test-data/irbuild-str.test
@@ -1025,3 +1025,153 @@ def is_digit(x):
 L0:
     r0 = CPyStr_IsDigit(x)
     return r0
+
+[case testStrIndexEqLiteral_64bit]
+def is_comma(s: str, i: int) -> bool:
+    return s[i] == ","
+def is_comma_swapped(s: str, i: int) -> bool:
+    return "," == s[i]
+def is_comma_ne(s: str, i: int) -> bool:
+    return s[i] != ","
+[out]
+def is_comma(s, i):
+    s :: str
+    i :: int
+    r0 :: native_int
+    r1 :: bit
+    r2, r3 :: i64
+    r4 :: ptr
+    r5 :: c_ptr
+    r6, r7 :: i64
+    r8, r9 :: bool
+    r10 :: short_int
+    r11 :: bit
+L0:
+    r0 = i & 1
+    r1 = r0 == 0
+    if r1 goto L1 else goto L2 :: bool
+L1:
+    r2 = i >> 1
+    r3 = r2
+    goto L3
+L2:
+    r4 = i ^ 1
+    r5 = r4
+    r6 = CPyLong_AsInt64(r5)
+    r3 = r6
+    keep_alive i
+L3:
+    r7 = CPyStr_AdjustIndex(s, r3)
+    r8 = CPyStr_RangeCheck(s, r7)
+    if r8 goto L5 else goto L4 :: bool
+L4:
+    r9 = raise IndexError('index out of range')
+    unreachable
+L5:
+    r10 = CPyStr_GetItemUnsafeAsInt(s, r7)
+    r11 = int_eq r10, 88
+    return r11
+def is_comma_swapped(s, i):
+    s :: str
+    i :: int
+    r0 :: native_int
+    r1 :: bit
+    r2, r3 :: i64
+    r4 :: ptr
+    r5 :: c_ptr
+    r6, r7 :: i64
+    r8, r9 :: bool
+    r10 :: short_int
+    r11 :: bit
+L0:
+    r0 = i & 1
+    r1 = r0 == 0
+    if r1 goto L1 else goto L2 :: bool
+L1:
+    r2 = i >> 1
+    r3 = r2
+    goto L3
+L2:
+    r4 = i ^ 1
+    r5 = r4
+    r6 = CPyLong_AsInt64(r5)
+    r3 = r6
+    keep_alive i
+L3:
+    r7 = CPyStr_AdjustIndex(s, r3)
+    r8 = CPyStr_RangeCheck(s, r7)
+    if r8 goto L5 else goto L4 :: bool
+L4:
+    r9 = raise IndexError('index out of range')
+    unreachable
+L5:
+    r10 = CPyStr_GetItemUnsafeAsInt(s, r7)
+    r11 = int_eq r10, 88
+    return r11
+def is_comma_ne(s, i):
+    s :: str
+    i :: int
+    r0 :: native_int
+    r1 :: bit
+    r2, r3 :: i64
+    r4 :: ptr
+    r5 :: c_ptr
+    r6, r7 :: i64
+    r8, r9 :: bool
+    r10 :: short_int
+    r11 :: bit
+L0:
+    r0 = i & 1
+    r1 = r0 == 0
+    if r1 goto L1 else goto L2 :: bool
+L1:
+    r2 = i >> 1
+    r3 = r2
+    goto L3
+L2:
+    r4 = i ^ 1
+    r5 = r4
+    r6 = CPyLong_AsInt64(r5)
+    r3 = r6
+    keep_alive i
+L3:
+    r7 = CPyStr_AdjustIndex(s, r3)
+    r8 = CPyStr_RangeCheck(s, r7)
+    if r8 goto L5 else goto L4 :: bool
+L4:
+    r9 = raise IndexError('index out of range')
+    unreachable
+L5:
+    r10 = CPyStr_GetItemUnsafeAsInt(s, r7)
+    r11 = int_ne r10, 88
+    return r11
+
+[case testStrIndexEqLiteralNoSpecialize]
+def two_char_literal(s: str, i: int) -> bool:
+    # Multi-char literals don't match the specialization; falls through to
+    # the generic str equality path.
+    return s[i] == "ab"
+def empty_literal(s: str, i: int) -> bool:
+    # Empty string literals also fall through; the generic path returns False.
+    return s[i] == ""
+[out]
+def two_char_literal(s, i):
+    s :: str
+    i :: int
+    r0, r1 :: str
+    r2 :: bool
+L0:
+    r0 = CPyStr_GetItem(s, i)
+    r1 = 'ab'
+    r2 = CPyStr_EqualLiteral(r0, r1, 2)
+    return r2
+def empty_literal(s, i):
+    s :: str
+    i :: int
+    r0, r1 :: str
+    r2 :: bool
+L0:
+    r0 = CPyStr_GetItem(s, i)
+    r1 = ''
+    r2 = CPyStr_EqualLiteral(r0, r1, 0)
+    return r2
diff --git a/mypyc/test-data/run-strings.test b/mypyc/test-data/run-strings.test
index ec662da96986..81b85580d7a7 100644
--- a/mypyc/test-data/run-strings.test
+++ b/mypyc/test-data/run-strings.test
@@ -1412,3 +1412,64 @@ def test_isdigit_strings() -> None:
     assert not "\u00e9\u00e8".isdigit()
     assert not "123\u00e9".isdigit()
     assert not "\U0001d7ce!".isdigit()
+
+[case testStrIndexEqLiteralSpecialize]
+from testutil import assertRaises
+
+# The specializer fires on the AST shape `IndexExpr == StrLiteral` (or the
+# symmetric swap, and `!=`). The literal has to be a real source-level
+# string literal (can't be passed in as a parameter), so each test
+# function pins one distinct shape.
+
+def eq_comma(s: str, i: int) -> bool:
+    # Specialized: s[i] == "x".
+    return s[i] == ","
+
+def ne_comma(s: str, i: int) -> bool:
+    # Specialized: s[i] != "x".
+    return s[i] != ","
+
+def comma_eq(s: str, i: int) -> bool:
+    # Specialized: "x" == s[i]. Operand-swap is normalized.
+    return "," == s[i]
+
+def eq_two_chars(s: str, i: int) -> bool:
+    # Not specialized: literal isn't 1 char. Falls through to the generic
+    # str compare, which returns False since s[i] is always 1 codepoint.
+    return s[i] == "ab"
+
+def eq_empty(s: str, i: int) -> bool:
+    # Not specialized: empty literal. Same fall-through.
+    return s[i] == ""
+
+def test_specialized_path() -> None:
+    s = "a,b"  # comma at index 1
+    assert eq_comma(s, 1)
+    assert not eq_comma(s, 0)
+    assert not eq_comma(s, 2)
+    # != inverts.
+    assert ne_comma(s, 0)
+    assert not ne_comma(s, 1)
+    # Literal on the LHS is normalized to the same shape.
+    assert comma_eq(s, 1)
+    assert not comma_eq(s, 0)
+
+def test_negative_index_is_adjusted() -> None:
+    s = "a,b"
+    assert eq_comma(s, -2)        # -2 -> 1 (',')
+    assert not eq_comma(s, -1)    # -1 -> 2 ('b')
+
+def test_non_1char_literal_falls_through() -> None:
+    s = "a,b"
+    # Generic str compare answers False because s[i] has length 1.
+    assert not eq_two_chars(s, 0)
+    assert not eq_two_chars(s, 1)
+    assert not eq_empty(s, 0)
+
+def test_out_of_range_raises_indexerror() -> None:
+    # Bounds-check semantics match the unspecialized s[i] path.
+    s = "a,b"
+    with assertRaises(IndexError):
+        eq_comma(s, 3)
+    with assertRaises(IndexError):
+        eq_comma(s, -4)