diff --git a/pymrio/core/mriosystem.py b/pymrio/core/mriosystem.py
index 4929dc20..9781071e 100644
--- a/pymrio/core/mriosystem.py
+++ b/pymrio/core/mriosystem.py
@@ -55,6 +55,11 @@
 #     warnings.warn(message, DeprecationWarning, stacklevel=2)
 
 
+# Constants for column name validation
+ALTERNATIVE_REGION_NAMES = ["country", "countries", "regions", "reg", "location"]
+ALTERNATIVE_SECTOR_NAMES = ["sectors", "industry", "industries", "sec", "activity"]
+
+
 # Exceptions
 class ResetError(Exception):
     """Base class for errors while reseting the system."""
@@ -1788,12 +1793,48 @@ def characterize(
             )
             return ret_value(validation=validation, extension=None)
 
-        fac_calc = (
-            factors.set_index(index_col + [characterized_name_column])
-            .loc[:, characterization_factors_column]
-            .unstack(characterized_name_column)
-            .fillna(0)
-        )
+        # Check for duplicate indices before unstacking
+        # This can happen if region/sector columns are not named correctly
+        factors_indexed = factors.set_index(index_col + [characterized_name_column])
+
+        if factors_indexed.index.duplicated().any():
+            # Build helpful error message
+            error_msg = (
+                "Duplicate indices found in characterization factors. "
+                "This typically occurs when region or sector specific characterization factors "
+                "are provided but the column names don't match pymrio's expectations.\n\n"
+                "Expected column names:\n"
+                "  - 'region' (lowercase) for region-specific factors\n"
+                "  - 'sector' (lowercase) for sector-specific factors\n\n"
+                f"Current columns in factors dataframe: {list(factors.columns)}\n\n"
+            )
+
+            # Check for case mismatches
+            possible_region_cols = [col for col in factors.columns if col.lower() == "region" and col != "region"]
+            possible_sector_cols = [col for col in factors.columns if col.lower() == "sector" and col != "sector"]
+
+            if possible_region_cols:
+                error_msg += f"Found possible region column with different case: {possible_region_cols}\n"
+                error_msg += "Please rename it to 'region' (lowercase).\n"
+            if possible_sector_cols:
+                error_msg += f"Found possible sector column with different case: {possible_sector_cols}\n"
+                error_msg += "Please rename it to 'sector' (lowercase).\n"
+
+            # Check for alternative column names if no case mismatch found
+            if not possible_region_cols and not possible_sector_cols:
+                found_region_alternatives = [col for col in factors.columns if col.lower() in ALTERNATIVE_REGION_NAMES]
+                found_sector_alternatives = [col for col in factors.columns if col.lower() in ALTERNATIVE_SECTOR_NAMES]
+
+                if found_region_alternatives:
+                    error_msg += f"Found possible alternative region column names: {found_region_alternatives}\n"
+                    error_msg += "Please rename to 'region' (lowercase) if these are region identifiers.\n"
+                if found_sector_alternatives:
+                    error_msg += f"Found possible alternative sector column names: {found_sector_alternatives}\n"
+                    error_msg += "Please rename to 'sector' (lowercase) if these are sector identifiers.\n"
+
+            raise ValueError(error_msg)
+
+        fac_calc = factors_indexed.loc[:, characterization_factors_column].unstack(characterized_name_column).fillna(0)
 
         new_ext = Extension(name=name)
 
diff --git a/tests/test_core.py b/tests/test_core.py
index 9a616b01..6b280a36 100644
--- a/tests/test_core.py
+++ b/tests/test_core.py
@@ -747,6 +747,56 @@ def test_characterize_extension_over_extensions(fix_testmrio):
     pdt.assert_frame_equal(ex_reg_one.unit, ex_reg_method.unit)
 
 
+def test_characterize_error_wrong_column_names(fix_testmrio):
+    """Test improved error message when region/sector column names are wrong."""
+    tmrio = fix_testmrio.testmrio
+
+    # Load region-specific factors
+    factors_reg_spec = pd.read_csv(
+        Path(PYMRIO_PATH["test_mrio"] / Path("concordance") / "emissions_charact_reg_spec.tsv"),
+        sep="\t",
+    )
+
+    # Test case 1: Wrong case for region column (Region instead of region)
+    factors_wrong_case = factors_reg_spec.copy()
+    factors_wrong_case = factors_wrong_case.rename(columns={"region": "Region"})
+
+    with pytest.raises(ValueError) as exc_info:
+        tmrio.emissions.characterize(factors_wrong_case)
+
+    error_msg = str(exc_info.value)
+    assert "Duplicate indices found" in error_msg
+    assert "column names don't match pymrio's expectations" in error_msg
+    assert "'region' (lowercase)" in error_msg
+    assert "Found possible region column with different case: ['Region']" in error_msg
+
+    # Test case 2: Alternative column name (country instead of region)
+    factors_country = factors_reg_spec.copy()
+    factors_country = factors_country.rename(columns={"region": "country"})
+
+    with pytest.raises(ValueError) as exc_info:
+        tmrio.emissions.characterize(factors_country)
+
+    error_msg = str(exc_info.value)
+    assert "Duplicate indices found" in error_msg
+    assert "Found possible alternative region column names: ['country']" in error_msg
+
+    # Test case 3: Abbreviated column name (reg instead of region)
+    factors_reg = factors_reg_spec.copy()
+    factors_reg = factors_reg.rename(columns={"region": "reg"})
+
+    with pytest.raises(ValueError) as exc_info:
+        tmrio.emissions.characterize(factors_reg)
+
+    error_msg = str(exc_info.value)
+    assert "Duplicate indices found" in error_msg
+    assert "Found possible alternative region column names: ['reg']" in error_msg
+
+    # Test case 4: Verify correct column names still work
+    result = tmrio.emissions.characterize(factors_reg_spec)
+    assert result.extension is not None
+
+
 def test_extension_convert_simple(fix_testmrio):
     """Testing the convert function within extensions object."""
     tt_pre = fix_testmrio.testmrio.copy()