diff --git a/docs/changelog.md b/docs/changelog.md
index 31cec0b2..879fbf43 100644
--- a/docs/changelog.md
+++ b/docs/changelog.md
@@ -16,6 +16,7 @@ See the [Contributing Guide](contributing.md) for details.
 
 * Fix a regression related to comment handling (#1590).
 * More reliable fix for `</` (#1593).
+* Prevent mixed `=` and `-` characters in Setext-style headers (#1606).
 
 ## [3.10.1] - 2026-01-21
 
diff --git a/markdown/blockprocessors.py b/markdown/blockprocessors.py
index 3ed4cf07..71d8854e 100644
--- a/markdown/blockprocessors.py
+++ b/markdown/blockprocessors.py
@@ -494,7 +494,7 @@ class SetextHeaderProcessor(BlockProcessor):
     """ Process Setext-style Headers. """
 
     # Detect Setext-style header. Must be first 2 lines of block.
-    RE = re.compile(r'^.*?\n[=-]+[ ]*(\n|$)', re.MULTILINE)
+    RE = re.compile(r'^.*?\n(?:[=]+|[-]+)[ ]*(\n|$)', re.MULTILINE)
 
     def test(self, parent: etree.Element, block: str) -> bool:
         return bool(self.RE.match(block))
diff --git a/tests/test_syntax/blocks/test_headers.py b/tests/test_syntax/blocks/test_headers.py
index da2ca14f..b1992ad3 100644
--- a/tests/test_syntax/blocks/test_headers.py
+++ b/tests/test_syntax/blocks/test_headers.py
@@ -109,6 +109,58 @@ def test_setext_h2_followed_by_p(self):
 
     # TODO: fix this
     # see https://johnmacfarlane.net/babelmark2/?normalize=1&text=Paragraph%0AAn+H1%0A%3D%3D%3D%3D%3D
+
+    def test_setext_mixed_chars_not_h1(self):
+        """Mixed = and - chars should not form a valid H1."""
+        self.assertMarkdownRenders(
+            self.dedent(
+                """
+                This is not an H1
+                =-
+                """
+            ),
+            self.dedent(
+                """
+                <p>This is not an H1
+                =-</p>
+                """
+            )
+        )
+
+    def test_setext_mixed_chars_not_h2(self):
+        """Mixed - and = chars should not form a valid H2."""
+        self.assertMarkdownRenders(
+            self.dedent(
+                """
+                This is not an H2
+                -=
+                """
+            ),
+            self.dedent(
+                """
+                <p>This is not an H2
+                -=</p>
+                """
+            )
+        )
+
+    def test_setext_mixed_multiple_chars(self):
+        """Multiple mixed = and - chars should not form a valid H1/H2."""
+        self.assertMarkdownRenders(
+            self.dedent(
+                """
+                Not a Header
+                =-=-
+                """
+            ),
+            self.dedent(
+                """
+                <p>Not a Header
+                =-=-</p>
+                """
+            )
+        )
+
     @unittest.skip('This is broken in Python-Markdown')
     def test_p_followed_by_setext_h1(self):
         self.assertMarkdownRenders(