A prospective randomized study was performed to assess the value of routine intraoperative cholangiography (IOC) during cholecystectomy for gallstone disease. Four hundred and fifty-seven consecutive patients were screened for the presence of 11 predefined clinical criteria assumed to indicate choledocholithiasis. Two hundred and eighty patients who had no positive criteria and in whom preoperative endoscopic retrograde cholangiography had not been performed were randomized at the operating table to the IOC or no-IOC group. Follow-up was performed 6 to 8 years after the operation with a questionnaire and by use of clinical, biochemical, and radiologic investigations as indicated. Multivariate analysis was used to identify independent predictors of choledocholithiasis and the combination of criteria having the best predictive ability. The frequency of common bile duct calculi at operation was significantly correlated with age and with all clinical criteria except recent or present pancreatitis. However, only serum bilirubin level, cystic duct diameter, demonstration of common bile duct calculi on preoperative imaging or intraoperative palpation, and age at operation were independent predictors of choledocholithiasis. The overall best subset of clinical indicators contained all criteria with the exception of pancreatitis and alkaline phosphatase level. Negative predictive ability of the set of criteria was 100% for patients up to 60 years of age and 97% for patients older than 60 years at the time of operation. No case of residual common bile duct calculi was present in the IOC and no-IOC groups at follow-up. Our data strongly support a policy of performing IOC during cholecystectomy only when clinical criteria suggest the presence of common bile duct abnormalities or to clarify ductal anatomy.