Background: ERCP is frequently complicated by pancreatitis. The aims of this study were to assess the efficacy of somatostatin and gabexate for prevention of post-ERCP pancreatitis in high-risk patients and to determine predisposing factors for post-ERCP pancreatitis. A meta-analysis was conducted of all published studies on the use of somatostatin or gabexate for prevention of post-ERCP pancreatitis. Methods: A double blind, multicenter, placebo-controlled trial was conducted in patients at high risk for post-ERCP pancreatitis. Patients were randomized to receive an intravenous infusion of somatostatin (750 mg), gabexate (500 mg), or placebo that was started 30 minutes before endoscopy and continued for 2 hours afterward. Patients were evaluated clinically and serum amylase levels determined at 4 and 24 hours after endoscopy. Results: No significant difference in the occurrence of pancreatitis, hyperamylasemia, or abdominal pain was observed among placebo-, gabexate-, and somatostatin-treated patients. A sphincterotomy longer than 2 cm (p = 0.0001), more than 3 pancreatic injections (p = 0.0001), and unsuccessful cannulation (p = 0.008) were predictive of post-ERCP pancreatitis. Hyperamylasemia was predicted by more than 3 pancreatic injections (p = 0.0001) and sphincterotomy (p = 0.02). The meta-analysis of trials of short-term infusion of gabexate or somatostatin did not show efficacy for either drug. Conclusions: Short-term administration of gabexate or somatostatin in patients at high risk for pancreatitis is ineffective for prevention of ERCP-induced pancreatitis. Pancreatic injury is related to maneuvers used to obtain biliary access rather than to any patient characteristic or endoscopist experience. (Gastrointest Endosc 2002;56:488-95.)