Background: Post-ERCP pancreatitis is poorly understood.The goal of this study was to comprehensively evaluate potential procedure- and patient-related risk factors for post-ERCP pancreatitis over a wide spectrum of centers. Methods: Consecutive ERCP procedures were prospectively studied at 11 centers (6 private, 5 university). Complications were assessed at 30 days by using established consensus criteria. Results: Pancreatitis occurred after 131 (6.7%) of 1963 consecutive ERCP procedures (mild 70, moderate 55, severe 6). By univariate analysis, 23 of 32 investigated variables were significant. Multivariate risk factors with adjusted odds ratios (OR) were prior ERCP-induced pancreatitis (OR 5.4), suspected sphincter of Oddi dysfunction (OR 2.6), female gender (OR 2.5), normal serum bilirubin (OR 1.9), absence of chronic pancreatitis (OR 1.9), biliary sphincter balloon dilation (OR 4.5), difficult cannulation (OR 3.4), pancreatic sphincterotomy (OR 3.1), and 1 or more injections of contrast into the pancreatic duct (OR 2.7). Small bile duct diameter, sphincter of Oddi manometry, biliary sphincterotomy, and lower ERCP case volume were not multivariate risk factors for pancreatitis, although endoscopists performing on average more than 2 ERCPs per week had significantly greater success at bile duct cannulation (96.5% versus 91.5%, p = 0.0001). Combinations of patient characteristics including female gender, normal serum bilirubin, recurrent abdominal pain, and previous post-ERCP pancreatitis placed patients at increasingly higher risk of pancreatitis, regardless of whether ERCP was diagnostic, manometric, or therapeutic. Conclusions: Patient-related factors are as important as procedure-related factors in determining risk for post-ERCP pancreatitis. These data emphasize the importance of careful patient selection as well as choice of technique in the avoidance of post-ERCP pancreatitis.