BACKGROUND AND AIMS: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis can be reduced following endoscopic papillary balloon dilation with the placement of an endoscopic nasobiliary drainage (ENBD) catheter. The aim of this study was to determine whether the placement of an ENBD reduces the risk of post-ERCP pancreatitis following endoscopic papillary large balloon dilation together with endoscopic biliary sphincterotomy. METHODS: A total of 160 patients with bile duct stones were randomly assigned (1:1) to an ENBD group or no-ENBD group. The primary outcome of this study was the incidence of post-ERCP pancreatitis. The secondary outcome was the incidence of post-ERCP hyperamylasemia. RESULTS: In total, 160 patients were randomized, and 155 were found to be eligible for the analysis. The two groups were similar regarding clinical and demographic factors as well as patient- and procedure-related risk factors for post-ERCP pancreatitis. Post-ERCP pancreatitis developed in 9 patients, that is, 8/77 (10.4%) of the control group and 1/78 (1.28%) of the ENBD group (p = .018; per protocol analysis). Intention to treat analysis also revealed that ENBD reduced the rate of post-ERCP pancreatitis (8/80 (10%) in the control group vs. 1/80 (1.25%) the ENBD group (p = .034)). Multivariate regression analysis identified not undergoing ENBD as an independent risk factor for post-ERCP pancreatitis (ENBD compared with no-ENBD: OR 0.087, 95% CI 0.011-0.734; p = .025). CONCLUSION: This study demonstrated that placement of an ENBD was effective and safe for the prevention of post-ERCP pancreatitis in patients undergoing endoscopic papillary large balloon dilation together with endoscopic biliary sphincterotomy.