diff --git a/pydeseq2/ds.py b/pydeseq2/ds.py
index c3f10a19..cc7a1321 100644
--- a/pydeseq2/ds.py
+++ b/pydeseq2/ds.py
@@ -528,14 +528,13 @@ def _independent_filtering(self) -> None:
             if not U2.empty:
                 result.loc[use, i] = false_discovery_control(U2, method="bh")
         num_rej = (result < self.alpha).sum(0).values
-        lowess_res = lowess(num_rej, theta, frac=1 / 5)
+        lowess_res = lowess(theta, num_rej, frac=1 / 5)
 
         if num_rej.max() <= 10:
             j = 0
         else:
-            residual = num_rej[num_rej > 0] - lowess_res[num_rej > 0, 1]
-            thresh = lowess_res[:, 1].max() - np.sqrt(np.mean(residual**2))
-
+            residual = num_rej[num_rej > 0] - lowess_res[num_rej > 0]
+            thresh = lowess_res.max() - np.sqrt(np.mean(residual**2))
             if np.any(num_rej > thresh):
                 j = np.where(num_rej > thresh)[0][0]
             else:
diff --git a/pydeseq2/utils.py b/pydeseq2/utils.py
index 7e69edc9..ce54200a 100644
--- a/pydeseq2/utils.py
+++ b/pydeseq2/utils.py
@@ -1590,7 +1590,10 @@ def lowess(
 
         residuals = targets - yest
         s = np.median(np.abs(residuals))
-        delta = np.clip(residuals / (6.0 * s), -1, 1)
+        if s == 0:
+            delta = (np.abs(residuals) > 0).astype(float)
+        else:
+            delta = np.clip(residuals / (6.0 * s), -1, 1)
         delta = (1 - delta**2) ** 2
 
     return yest
diff --git a/tests/data/wide/r_test_dispersions.csv b/tests/data/wide/r_test_dispersions.csv
new file mode 100644
index 00000000..91739e86
--- /dev/null
+++ b/tests/data/wide/r_test_dispersions.csv
@@ -0,0 +1,51 @@
+"","x"
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diff --git a/tests/data/wide/r_test_res.csv b/tests/data/wide/r_test_res.csv
new file mode 100644
index 00000000..65760c85
--- /dev/null
+++ b/tests/data/wide/r_test_res.csv
@@ -0,0 +1,51 @@
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diff --git a/tests/data/wide/r_test_size_factors.csv b/tests/data/wide/r_test_size_factors.csv
new file mode 100644
index 00000000..26084b2b
--- /dev/null
+++ b/tests/data/wide/r_test_size_factors.csv
@@ -0,0 +1,31 @@
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diff --git a/tests/data/wide/test_counts.csv b/tests/data/wide/test_counts.csv
new file mode 100644
index 00000000..b842102a
--- /dev/null
+++ b/tests/data/wide/test_counts.csv
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+"gene43",28,129,70,132,68,155,58,70,35,46,28,47,66,81,106,46,22,34,9,36,17,59,11,18,13,20,27,20,12,58
+"gene44",36,45,53,63,23,94,33,43,86,30,16,75,24,39,32,6,43,27,33,76,12,84,82,112,51,23,15,15,10,22
+"gene45",3,1,2,42,16,5,9,33,1,19,11,4,3,30,3,9,0,5,4,18,1,8,3,9,2,28,2,6,2,11
+"gene46",3,2,4,2,1,5,1,6,6,5,1,19,5,2,0,0,4,4,0,4,7,1,0,4,3,9,3,5,1,4
+"gene47",26,15,18,10,33,10,8,8,6,8,10,8,28,8,19,46,294,93,131,25,181,59,57,21,118,58,128,56,124,17
+"gene48",37,71,29,25,64,31,64,26,34,18,46,33,48,29,45,31,40,28,30,30,88,16,54,78,29,26,81,10,72,38
+"gene49",6,17,9,16,8,3,18,1,29,4,9,3,2,6,8,4,4,0,2,1,6,2,5,0,5,0,12,2,8,4
+"gene50",86,64,89,81,11,36,22,31,47,30,51,32,9,32,37,14,21,21,9,10,16,13,17,11,36,15,13,10,17,6
diff --git a/tests/data/wide/test_metadata.csv b/tests/data/wide/test_metadata.csv
new file mode 100644
index 00000000..a302d4e9
--- /dev/null
+++ b/tests/data/wide/test_metadata.csv
@@ -0,0 +1,31 @@
+"","condition","group"
+"sample1","A","X"
+"sample2","A","Y"
+"sample3","A","X"
+"sample4","A","Y"
+"sample5","A","X"
+"sample6","A","Y"
+"sample7","A","X"
+"sample8","A","Y"
+"sample9","A","X"
+"sample10","A","Y"
+"sample11","A","X"
+"sample12","A","Y"
+"sample13","A","X"
+"sample14","A","Y"
+"sample15","A","X"
+"sample16","B","Y"
+"sample17","B","X"
+"sample18","B","Y"
+"sample19","B","X"
+"sample20","B","Y"
+"sample21","B","X"
+"sample22","B","Y"
+"sample23","B","X"
+"sample24","B","Y"
+"sample25","B","X"
+"sample26","B","Y"
+"sample27","B","X"
+"sample28","B","Y"
+"sample29","B","X"
+"sample30","B","Y"
diff --git a/tests/test_pydeseq2.py b/tests/test_pydeseq2.py
index b58db574..900ede6f 100644
--- a/tests/test_pydeseq2.py
+++ b/tests/test_pydeseq2.py
@@ -173,7 +173,8 @@ def test_lfc_shrinkage(counts_df, metadata, tol=0.02):
     ).squeeze()
 
     r_dispersions = pd.read_csv(
-        os.path.join(test_path, "data/single_factor/r_test_dispersions.csv"), index_col=0
+        os.path.join(test_path, "data/single_factor/r_test_dispersions.csv"),
+        index_col=0,
     ).squeeze()
 
     dds = DeseqDataSet(counts=counts_df, metadata=metadata, design_factors="condition")
@@ -426,6 +427,50 @@ def test_continuous_lfc_shrinkage(tol=0.02):
     ).max() < tol
 
 
+def test_wide_deseq(
+    tol=0.02,
+):
+    """Test that the outputs of the DESeq2 function match those of the original R
+    package, up to a tolerance in relative error, on a dataset with more genes than
+    samples.
+    """
+
+    test_path = str(Path(os.path.realpath(tests.__file__)).parent.resolve())
+
+    counts_df = pd.read_csv(
+        os.path.join(test_path, "data/wide/test_counts.csv"), index_col=0
+    ).T
+
+    metadata = pd.read_csv(
+        os.path.join(test_path, "data/wide/test_metadata.csv"), index_col=0
+    )
+
+    # Load R results
+    r_res = pd.read_csv(os.path.join(test_path, "data/wide/r_test_res.csv"), index_col=0)
+
+    dds = DeseqDataSet(
+        counts=counts_df,
+        metadata=metadata,
+        design_factors=["group", "condition"],
+    )
+    dds.deseq2()
+
+    res = DeseqStats(dds)
+    res.summary()
+    res_df = res.results_df
+
+    # check that the same p-values are NaN
+    assert (res_df.pvalue.isna() == r_res.pvalue.isna()).all()
+    assert (res_df.padj.isna() == r_res.padj.isna()).all()
+
+    # Check that the same LFC, p-values and adjusted p-values are found (up to tol)
+    assert (
+        abs(r_res.log2FoldChange - res_df.log2FoldChange) / abs(r_res.log2FoldChange)
+    ).max() < tol
+    assert (abs(r_res.pvalue - res_df.pvalue) / r_res.pvalue).max() < tol
+    assert (abs(r_res.padj - res_df.padj) / r_res.padj).max() < tol
+
+
 def test_contrast(counts_df, metadata):
     """
     Check that the contrasts ['condition', 'B', 'A'] and ['condition', 'A', 'B'] give