Chenodeoxycholic acid (CDC) and ursodeoxycholic acid (UDC) have distinct physicochemical and metabolic properties which, being complementary, should favor more rapid removal of cholesterol from gallstones when both bile acids are administered together. To see if the combination is more effective and well tolerated, we have compared 5 mg/kg of CDC plus 5 mg/kg of UDC with a 10-mg/kg dose of UDC alone in 120 patients with radiolucent, sonographically confirmed gallstones and characteristics favoring complete dissolution. Ursodeoxycholic acid was chosen as the reference because it dissolves stones faster and is better tolerated than CDC. To minimize the influence of stone size, the major determinant of dissolution, patients were divided, on admission, into two groups according to the maximum stone diameter: 50 had stones less than or equal to 5 mm, 70 had stones greater than 5 mm but less than 15 mm. The effects of treatment on stone dissolution evaluated by cholecystography and ultrasonography at 6, 12, and 24 mo, were analyzed by the actuarial life-table method. In the group with smaller stones, significantly more patients had obtained complete dissolution after treatment with the combination (52%) than after treatment with UDC alone (24%) at 6 mo. After longer periods, results were still better with the combination, although the differences from UDC alone became smaller. In the patients with larger stones, rates of complete and partial dissolutions were higher after treatment with the combination (51% vs. 24% with UDC) at 6 mo and again the differences had become smaller after longer treatment. Although not statistically significant, stone calcification occurred more often with UDC (7 cases) than with the combination (1 case). We conclude that CDC plus UDC is preferable to UDC alone because it dissolves stones more quickly, with a lower incidence of stone calcification, and may result in reduced cost of treatment.