Introduction. An increased risk of gallstone (GS) formation has been linked to obesity and to episodes of rapid and significant weight loss. Previous reports have suggested that bile salt therapy (ursodeoxycholic acid) or prostaglandin inhibition (ibuprofen) may prevent gallstone formation in this high-risk group. The purpose of this study was to investigate GS prevention following bariatric surgery. Design. Randomized double blind controlled trial. Methods. Sixty patients without gallstones preoperatively (gender, 9 male, 51 female; average preop wt, 349.6 lb; mean age, 38 years) were randomly assigned to receive urso (600 mg/day, n = 20), ibuprofen (600 mg/d, n = 20), or placebo (n = 20). At the time of standard open gastric bypass, intraoperative ultrasonography confirmed the absence of stones or microcalculi, and bile samples were collected via puncture of the gallbladder for bile lipid analysis. Following recovery and resumption of a bariatric diet, study medication was prescribed for the first 6 months postop. Gallbladder emptying and GS formation were assessed using ultrasonograms preop and at 3, 6, 9, and 12 months postop (gallbladder emptying following a high-fat liquid test meal was assessed preop, and at 3 and 6 months postop). Results. Forty-one (68.3%, 8 male, 33 female) of the original 60 patients completed all phases of the study (15 urso, 15 ibuprofen, 11 placebo). The average weight loss was 98.5 ± 7.2 lb over the 12-month period following bariatric surgery. Twenty-nine (71%) of 41 patients who completed the study developed GS. Of those who formed stones, 12 (41%) developed symptomatic GS and 8/12 (67%) underwent cholecystectomy (4 refused operation). Preoperative gallbladder emptying studies showed no differences in emptying between groups (urso 29%, ibuprofen 32%, and placebo 30%). There was no correlation found between the cholesterol saturation index (CSI mean 205.15, range 67-360) and the incidence of GS. There was a statistical difference (P < 0.01) between the ursodeoxycholic acid group and the ibuprofen group with respect to the incidence of stone formation. There was correlation between weight loss (mean 99 lb, range 21-278 lb) and GS formation, in that patients who lost more weight had a greater tendency to form gallstones. Complete medical compliance was achieved in only 17/60 (28%) of patients originally enrolled. Conclusions. This pilot study confirms the high incidence of gallstone formation (71% of assessed patients) associated with rapid weight loss in patients undergoing gastric bypass. Despite active enrollment in a supervised prevention trial, the two therapies investigated to reduce gallstone formation were not efficacious, likely because compliance with medical therapy was poor. These findings highlight the significant risk of gallstone formation in this patient cohort even when prevention strategies are utilized.