diff --git a/news/118-fix-ligand-cofactor-selection.rst b/news/118-fix-ligand-cofactor-selection.rst
new file mode 100644
index 0000000..2aa6035
--- /dev/null
+++ b/news/118-fix-ligand-cofactor-selection.rst
@@ -0,0 +1,6 @@
+**Fixed:**
+
+* ``gather_rms_data`` now correctly identifies the ligand when cofactors
+  share the same residue name ``UNK``. The ligand is auto-detected using
+  hybrid topology tempfactors (b-factors), while custom ``ligand_selection``
+  strings are still respected.
diff --git a/src/openfe_analysis/rmsd.py b/src/openfe_analysis/rmsd.py
index 9c86200..71eba08 100644
--- a/src/openfe_analysis/rmsd.py
+++ b/src/openfe_analysis/rmsd.py
@@ -256,6 +256,63 @@ def _single_frame(self) -> None:
         )
 
 
+def _select_ligand(
+    universe: mda.Universe,
+    ligand_selection: str,
+) -> mda.AtomGroup:
+    """
+    Select the ligand AtomGroup, handling cofactors with the same resname.
+
+    In OpenFE hybrid topologies, the alchemical ligand atoms have tempfactors
+    (b-factors) of 0.25, 0.5, or 0.75, while cofactors typically have
+    tempfactors of 0.0. When the default selection `"resname UNK"` matches
+    multiple residues, the ligand is identified as the residue containing
+    atoms with tempfactors strictly between 0 and 1.
+
+    Parameters
+    ----------
+    universe : mda.Universe
+        The MDAnalysis universe to select from.
+    ligand_selection : str
+        MDAnalysis selection string. If this is the default
+        `"resname UNK"` and multiple residues match, the ligand is
+        auto-detected using tempfactors.
+
+    Returns
+    -------
+    mda.AtomGroup
+        The selected ligand atoms.
+    """
+    ligand = universe.select_atoms(ligand_selection)
+
+    # If user provided a custom selection, only one residue matches,
+    # or no atoms matched, return the selection as-is.
+    if ligand_selection != "resname UNK" or len(ligand.residues) <= 1 or ligand.n_atoms == 0:
+        return ligand
+
+    # Multiple UNK residues: identify the ligand by hybrid tempfactors.
+    # In OpenFE hybrid topologies, alchemical atoms have tempfactors
+    # of 0.25 (state A unique), 0.5 (shared), or 0.75 (state B unique).
+    try:
+        has_tempfactors = True
+        universe.atoms.tempfactors
+    except AttributeError:
+        has_tempfactors = False
+
+    if has_tempfactors:
+        hybrid_residues = [
+            res for res in ligand.residues if any(0.0 < tf < 1.0 for tf in res.atoms.tempfactors)
+        ]
+
+        if len(hybrid_residues) == 1:
+            return hybrid_residues[0].atoms
+        elif len(hybrid_residues) > 1:
+            return max(hybrid_residues, key=lambda r: len(r.atoms)).atoms
+
+    # Fallback: no hybrid residues found or no tempfactors available
+    return max(ligand.residues, key=lambda r: len(r.atoms)).atoms
+
+
 def gather_rms_data(
     pdb_topology: pathlib.Path,
     dataset: pathlib.Path,
@@ -335,7 +392,7 @@ def gather_rms_data(
             universe = create_universe_single_state(u_top._topology, ds, state_idx)
 
             prot = universe.select_atoms(protein_selection)
-            ligand = universe.select_atoms(ligand_selection)
+            ligand = _select_ligand(universe, ligand_selection)
 
             if prot:
                 apply_complex_alignment_transformations(
diff --git a/src/openfe_analysis/tests/test_gather_rms_data.py b/src/openfe_analysis/tests/test_gather_rms_data.py
index 9734548..5f31747 100644
--- a/src/openfe_analysis/tests/test_gather_rms_data.py
+++ b/src/openfe_analysis/tests/test_gather_rms_data.py
@@ -1,7 +1,8 @@
+import MDAnalysis as mda
 import numpy as np
 from numpy.testing import assert_allclose
 
-from openfe_analysis.rmsd import gather_rms_data
+from openfe_analysis.rmsd import _select_ligand, gather_rms_data
 
 
 def test_gather_rms_data_regression(simulation_nc, hybrid_system_pdb):
@@ -31,7 +32,6 @@ def test_gather_rms_data_regression(simulation_nc, hybrid_system_pdb):
         rtol=1e-3,
     )
     assert len(output["protein_2D_RMSD"]) == 3
-    # 15 entries because 6 * 6 frames // 2
     assert len(output["protein_2D_RMSD"][0]) == 15
     assert_allclose(
         output["protein_2D_RMSD"][0][:6],
@@ -49,7 +49,6 @@ def test_gather_rms_data_regression_skippednc(simulation_skipped_nc, hybrid_syst
 
     assert_allclose(output["time(ps)"], np.arange(0, 5001, 100))
     assert len(output["protein_RMSD"]) == 11
-    # RMSD is low for this multichain protein
     assert_allclose(
         output["protein_RMSD"][0][:6],
         [0, 1.089747, 1.006143, 1.045068, 1.476353, 1.332893],
@@ -68,7 +67,6 @@ def test_gather_rms_data_regression_skippednc(simulation_skipped_nc, hybrid_syst
         rtol=1e-3,
     )
     assert len(output["protein_2D_RMSD"]) == 11
-    # 15 entries because 6 * 6 frames // 2
     assert len(output["protein_2D_RMSD"][0]) == 1275
     assert_allclose(
         output["protein_2D_RMSD"][0][:6],
@@ -82,13 +80,82 @@ def test_gather_rms_data_ligand_only(simulation_skipped_nc, hybrid_system_skippe
         hybrid_system_skipped_pdb,
         simulation_skipped_nc,
         skip=100,
-        protein_selection="resname DOESNOTEXIST",  # no protein
+        protein_selection="resname DOESNOTEXIST",
     )
 
-    # No protein results
     assert len(output["protein_RMSD"]) == 0
     assert len(output["protein_2D_RMSD"]) == 0
-
-    # Ligand results should still be present
     assert len(output["ligand_RMSD"]) > 0
     assert len(output["ligand_wander"]) > 0
+
+
+def _make_test_universe(tempfactors, resids, resnames=None):
+    n_atoms = len(tempfactors)
+    n_residues = len(set(resids))
+    unique_resids = list(dict.fromkeys(resids))
+    resid_to_idx = {r: i for i, r in enumerate(unique_resids)}
+    atom_resindex = [resid_to_idx[r] for r in resids]
+
+    if resnames is None:
+        resnames = ["UNK"] * n_residues
+
+    u = mda.Universe.empty(
+        n_atoms=n_atoms,
+        n_residues=n_residues,
+        atom_resindex=atom_resindex,
+    )
+    u.add_TopologyAttr("names", [f"C{i}" for i in range(1, n_atoms + 1)])
+    u.add_TopologyAttr("resnames", resnames)
+    u.add_TopologyAttr("resids", unique_resids)
+    u.add_TopologyAttr("tempfactors", tempfactors)
+    return u
+
+
+def test_select_ligand_single_unk():
+    u = _make_test_universe(
+        tempfactors=[0.25, 0.50, 0.75],
+        resids=[1, 1, 1],
+    )
+    ligand = _select_ligand(u, "resname UNK")
+    assert len(ligand) == 3
+    assert set(ligand.resids) == {1}
+
+
+def test_select_ligand_cofactor_present():
+    u = _make_test_universe(
+        tempfactors=[0.25, 0.50, 0.75, 0.00],
+        resids=[1, 1, 1, 2],
+    )
+    ligand = _select_ligand(u, "resname UNK")
+    assert len(ligand) == 3
+    assert set(ligand.resids) == {1}
+
+
+def test_select_ligand_multiple_hybrid():
+    u = _make_test_universe(
+        tempfactors=[0.25, 0.50, 0.75, 0.25, 0.50],
+        resids=[1, 1, 1, 2, 2],
+    )
+    ligand = _select_ligand(u, "resname UNK")
+    assert len(ligand) == 3
+    assert set(ligand.resids) == {1}
+
+
+def test_select_ligand_no_hybrid_fallback():
+    u = _make_test_universe(
+        tempfactors=[0.00, 0.00, 0.00, 0.00],
+        resids=[1, 1, 2, 2],
+    )
+    ligand = _select_ligand(u, "resname UNK")
+    assert len(ligand) == 2
+
+
+def test_select_ligand_custom_selection_unchanged():
+    u = _make_test_universe(
+        tempfactors=[0.25, 0.50, 0.75, 0.00],
+        resids=[1, 1, 1, 2],
+        resnames=["LIG", "LIG", "LIG", "COF"],
+    )
+    ligand = _select_ligand(u, "resname LIG")
+    assert len(ligand) == 3
+    assert set(ligand.resids) == {1}