AIM: To assess the efficacy of allopurinol to prevent hyperamylasemia and pancreatitis after endoscopic retrograde cholangiopancreatography (PEP). METHODS: One hundred and seventy patients were enrolled and randomized to two groups: a study group ( n = 85) who received 300 mg of oral allopurinol at 15 h and 3 h before endoscopic retrograde cholangiopancreatography (ERCP) and a control group ( n = 85) receiving an oral placebo at the same times. Main Outcome Measurements included serum amylase levels and the number severity of the episodes of pancreatitis. Serum amylase levels were classified as normal (＜150 IU/L) or hyperamylasemia (＞151 IU/L). Episodes of PEP were classified following Ranson's criteria and CT severity index. RESULTS: Gender distribution was similar between groups. Mean age was 53.5 ± 18.9 years for study group and 52.8 ± 19.8 years for controls. Also, the distribution of benign pathology was similar between groups. Hyperamylasemia was more common in the control group ( P = 0.003). Mild PEP developed in two patients from the study group (2.3%) and eight (9.4%) from control group ( P = 0.04), seven episodes were observed in high-risk patients of the control group (25%) and one in the allopurinol group (3.3%, P = 0.02). Risk factors for PEP were precut sphincterotomy ( P = 0.02),pancreatic duct manipulation ( P = 0.002) and multiple procedures ( P = 0.000). There were no deaths or side effects.CONCLUSION: Oral allopurinol before ERCP decreased the incidences of hyperamylasemia and pancreatitis in patients submitted to high-risk procedures.