A double-blind randomized, multicenter study was carried out to determine the efficacy and safety of ursodeoxycholic acid (UDCA) at 4 doses of 2.1 to 16.2 mg-kg−1 day−1, and chenodeoxycholic acid (CDCA) at the dose of 16.9 mg-kg−1 -day−1, in 197 patients treated for up to 1 year for radiolucent gallstones in functioning (opacified) gallbladders. There was confirmed complete dissolution in 5.9% of patients receiving UDCA at the dose of 2.1 mg-kg−1 day−1, 18.9% in those receiving 4.2, 28.9% in those receiving 8.4, 14.6% in those receiving 16.2, and 20.0% in patients receiving CDCA. Partial (over 50%) or complete dissolution occurred in 29.4% of patients receiving 2.1 mg-kg−1−day−1 of UDCA, 37.8% of those receiving 4.2, 55.2% in those receiving 8.4, 48.7% in those receiving 16.2, and 50.0% in patients receiving CDCA. Complete dissolution occurred significantly more frequently in small (less than 5 mm in diameter) than in large (5 to 15 and more than 15 mm) stones. There was no significant influence of treatment on serum cholesterol and triglycerides in any of the groups. Serum aminotransferases remained normal (or lower than twice the upper normal limit) in all patients treated with UDCA. Diarrhea leading to cessation of treatment occurred in 5% of patients receiving UDCA, but was significantly less frequent than in those receiving CDCA. These results confirm that, within a 1-year period, UDCA is equally effective and induces diarrhea less frequently than CDCA, with an optimal dose (8 mg-kg−1−day−1) approximately twice lower than that of CDCA.