BACKGROUND The purpose of this study was to evaluate the natural history of patients undergoing Roux-en-Y gastric bypass (RYGBP) with known asymptomatic cholelithiasis in whom prophylactic cholecystectomy was not performed at the time of surgery. METHODS The records of 144 consecutive patients from a single year experience in RYGBP surgery at the University of California, Davis Medical Center were reviewed. Patients undergoing RYGBP were routinely screened for cholelithiasis by ultrasound. Patients who did not have cholecystectomy were managed with ursodiol for 6 months postoperatively. RESULTS 13 males (9.0%) and 131 females (91%) underwent RYGBP. The mean age was 43 years (SD 8.55), and mean BMI was 46 kg/m2 (SD 6.5). The comorbidities of our patient population included diabetes (14%), hypertension (48%), gastroesophageal reflux disease (50%), dyslipidemia (35%), obstructive sleep apnea (31%), and musculoskeletal complaints (69%). 22 patients were diagnosed with cholelithiasis by ultrasonography preoperatively. 9 of these patients (41%) were symptomatic and underwent concurrent cholecystectomy and RYGBP. The remaining 13 patients (59%) had asymptomatic cholelithiasis preoperatively but did not undergo cholecystectomy at the time of surgery. Only one of these asymptomatic patients eventually developed symptoms necessitating cholecystectomy at up to 1 year follow-up. CONCLUSIONS Our data suggest that it may not be absolutely indicated to perform prophylactic cholecystectomy at the time of RYGBP surgery for asymptomatic cholelithiasis. We believe that this phenomenon needs to be further studied in a randomized trial.