Background: Pancreatitis is the most common major complication of ERCP. Efforts have been made to identify pharmacologic agents capable of reducing its incidence and severity. The aim of this trial was to determine whether prophylactic allopurinol, an inhibitor of oxygen-derived free radical production, would reduce the frequency and severity of post-ERCP pancreatitis. Methods A total of 701 patients were randomized to receive either allopurinol or placebo 4 hours and 1 hour before ERCP. A database was prospectively collected by a defined protocol on patients who underwent ERCP. Standardized criteria were used to diagnose and grade the severity of postprocedure pancreatitis.Results: The groups were similar with regard to patient demographics and to patient and procedure risk factors for pancreatitis. The overall incidence of pancreatitis was 12.55%. It occurred in 46 of 355 patients in the allopurinol group (12.96%) and in 42 of 346 patients in the control group (12.14%; p = 0.52). The pancreatitis was graded mild in 7.89%, moderate in 4.51%, and severe in 0.56% of the allopurinol group, and mild in 6.94%, moderate in 4.62%, and severe in 0.58% of the control group. There was no significant difference between the groups in the frequency or the severity of pancreatitis.Conclusions: Prophylactic oral allopurinol did not reduce the frequency or the severity of post-ERCP pancreatitis.