We carried out a retrospective cohort study on all patients undergoing sphincterotomy at our institution over a 4-year period. Major hemorrhage occurred in 10 of 189 patients (5.3%). Onset was usually delayed (mean, 3.0 days; range, 0-9 days). Six potential risk factors for postsphincterotomy hemorrhage were assessed by univariate and multivariate analysis. Three factors predicted postsphincterotomy hemorrhage: hemodialysis (relative risk, 8.4; 95% confidence interval, CI, 2.7-26.4), a prothrombin time prolonged at least 2 s above control (relative risk, 7.8; 95% CI, 2.4-25.6), and endoscopically observed bleeding at the time of sphincterotomy (relative risk, 5.9; 95% CI, 1.7-20.1). Features not independently associated with hemorrhage were sphincter of Oddi dysfunction, aspirin or nonsteroidal anti-inflammatory drug (NSAID) use within 1 week prior to sphincterotomy, and sphincterotomy length. When differentiated from endoscopically observed bleeding, clinically significant hemorrhage was usually a delayed complication, primarily in patients with hemostatic defects.