Background and Study Aims: The aims of the present study was to analyze the risk factors associated with complications of endoscopic sphincterotomy (ES). Patients and Methods: In all consecutive endoscopic sphincterotomies carried out between September 1994 and December 1996, the possible risk factors (12 patient-related factors and 12 procedure-related ones), as well as the concomitant medical treatment, indications, techniques, and success of endoscopic sphincterotomy were evaluated prospectively. Risk factors were analyzed on an exploratory basis using univariate methods. ″Potential risk factors″ (univariate, P < 0.1) underwent multivariate analysis to determine independent ″risk factors″ (multivariate, P < 0.05). In addition, the complication rate was calculated according to the number of potential risk factors present. Results: A total of 438 patients who underwent ES were analyzed. Complications occurred in 7.5 (n = 33; acute pancreatitis 4.3, hemorrhage 2.3, cholangitis 0.9, technical 0.2). Statistical analysis of the complications identified three independent risk factors (coagulopathy, patient age (≤ 60 years, pancreas divisum), and one protective factor (pancreatic duct obstruction). The frequency of acute pancreatitis was increased by two independent risk factors (pancreas divisum, ES frequency < 40 procedures/year) and was reduced if low-dose anticoagulation (unfractionated heparin or low-molecular weight heparin) was administered (0.9, one of 115 vs. 5.8, 18 of 313; P < 0.05). The effect of anticoagulation was not confounded by the presence or absence of other potential risk factors for acute pancreatitis. Neither the risk nor the severity of hemorrhage were increased by low-dose anticoagulation. Due to the low number of events, only potential risk factors for hemorrhage were identified (coagulopathy, intensive-care treatment). The overall complication rate and the incidence of pancreatitis and hemorrhage increased significantly depending on the number of simultaneous potential risk factors present (P < 0.0001). Conclusions: Patients at risk for complications after endoscopic sphincterotomy can be identified by risk factor analysis. These data suggest the hypothesis that low-dose anticoagulation prior to endoscopic sphincterotomy reduces the risk of acute pancreatitis after sphincterotomy.