BACKGOUND/AIMS: Pancreatitis is the most common and important complication of an endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to identify risk factors for post ERCP-pancreatitis in patients pretreated with nafamostat mesilate, a synthetic protease inhibitor. METHODS: A total of 247 patients who underwent an ERCP were evaluated prospectively. Potential risk factors of post-ERCP pancreatitis in patients pretreated with nafamostat mesilate were evaluated. RESULTS: Twenty-four patients (9.7%) and nine patients (3.6%) developed post-ERCP hyperamylasemia and pancreatitis, respectively. As determined by univariate analysis among the potential risk factors, we found a procedure time over 20 minutes, pancreatic duct cannulation over four times, prior post-ERCP pancreatitis and the absence of a common bile duct (CBD) stone as risk factors for post-ERCP hyperamylasemia. We also found a patient age under 60 years, a procedure time over 20 minutes, pancreatic duct cannulation over four times and the absence of a CBD stone as risk factors for post-ERCP pancreatitis (p<0.05). As determined by multivariate analysis, pancreatic cannulation over four times is independently associated with post-ERCP hyperamylasemia (p=0.038; OR, 5.165; 95% CI, 1.093~24.412) and post-ERCP pancreatitis (p=0.002; OR, 33.122; 95% CI, 3.526~311.138). CONCLUSIONS: A repeated pancreatic duct cannulation is the most important risk factor for post-ERCP pancreatitis in patients pretreated with nafamostat mesilate.