Background: Pancreatic sphincter hypertension increases the risk of pancreatitis in patients undergoing ERCP. Glyceryl trinitrate reduces sphincter of Odd! pressure. This study tested the hypothesis that transdermal glyceryl trinitrate could be effective in the prevention of post-ERCP pancreatitis. Methods: One hundred forty-four patients undergoing ERCP were randomized: 71 received a 15-mg glyceryl trinitrate patch (glyceryl trinitrate group) and 73 a placebo patch (control group). Results: In the control group, post-ERCP pancreatitis developed in 11 patients versus 3 in the glyceryl trinitrate group (p < 0.05). Twenty-four hour to baseline serum amylase and lipase ratios were lower in the glyceryl trinitrate group (respectively, 3.6 vs. 7.5, p < 0.05; and 5.3 vs. 27.7, p < 0.05). In a multivariate analysis, glyceryl trinitrate patch and the number of pancreatic injections, but not endoscopic sphincterotomy, were independent risk factors for post-ERCP pancreatitis. Conclusions: The results of this study suggest that use of a transdermal glyceryl trinitrate patch protects against post-ERCP pancreatitis.