diff --git a/docs/release-notes/3461.bugfix.md b/docs/release-notes/3461.bugfix.md
new file mode 100644
index 0000000000..8635c319cf
--- /dev/null
+++ b/docs/release-notes/3461.bugfix.md
@@ -0,0 +1 @@
+Fixes an error where `regress_out` would fail to work with `integer` types {smaller}`S Dicks`
diff --git a/src/scanpy/preprocessing/_simple.py b/src/scanpy/preprocessing/_simple.py
index 986a2cd386..a9a675724a 100644
--- a/src/scanpy/preprocessing/_simple.py
+++ b/src/scanpy/preprocessing/_simple.py
@@ -752,6 +752,9 @@ def regress_out(
     # if the regressors are not categorical and the matrix is not singular
     # use the shortcut numpy_regress_out
     if not variable_is_categorical and np.linalg.det(regressors.T @ regressors) != 0:
+        if np.issubdtype(X.dtype, np.integer):
+            target_dtype = np.float32 if X.dtype.itemsize <= 4 else np.float64
+            X = X.astype(target_dtype, order="C")
         X = _to_dense(X, order="C") if issparse(X) else X
         res = numpy_regress_out(X, regressors)