The safety and efficacy of gallbladder extracorporeal shock-wave lithotripsy combined with 600 mg/day ursodiol were examined in 85 patients with radiolucent gallstones, 15 with lightly calcified gallstones, and 12 with radiolucent stones pretreated for greater than or equal to 2 months with 600 mg/day ursodiol. Results were compared with those of a well-matched lithotripsy-eligible group of 32 subjects treated with ursodiol alone (no lithotripsy). Pretreatment with ursodiol significantly improved while gallstone calcification interfered with fragmentation. Small gallstone size and number also aided fragmentation. Biliary lithotripsy plus ursodiol increased efficacy twofold compared with ursodiol therapy alone (47% vs. 22% of subjects gallstone free; P less than 0.02). Gallstones did not disappear in any subject with calcified gallstones (P less than 0.001) vs. lithotripsy). Product-limit analysis showed that the efficacy for gallstone dissolution increases in the following order: ursodiol alone, lithotripsy-ursodiol, lithotripsy-ursodiol pretreated with ursodiol (P less than 0.02, pairwise). Similar mean gallstone-dissolution rate constants (stone size divided by time to disappear) of stone fragments and whole gallstones during ursodiol therapy suggest that most fragments disappear by dissolution not expulsion. This finding explains why fragmentation appears to be the key predictor of disappearance and even partial fragmentation accelerates gallstone clearance.