Background: Somatostatin is a potent inhibitor of pancreatic secretion and has been studied for its prophylactic effect on post-ERCP pancreatitis. However, results of previous trials have been inconclusive. Methods: A prospective double-blind controlled study was performed to evaluate the effectiveness of somatostatin in preventing post-ERCP pancreatitis. Post-ERCP enzyme elevation, abdominal pain and pancreatitis were evaluated and compared between 109 patients randomized to receive somatostatin infusion and 111 patients randomized to receive normal saline infusion (placebo); both started 30 minutes before ERCP and continued for 12 hours. Results: Post-ERCP elevation of serum amylase and lipase levels at 6 and 24 hours after ERCP was less frequent in the group given somatostatin but not statistically significant. There was a tendency toward lower mean serum amylase and lipase levels at 24 hours in patients given somatostatin, although the difference was not statistically significant either. Eight patients given somatostatin (7%) and 18 patients given placebo (16%) had significant abdominal pain after ERCP requiring analgesia (p = 0.04). The frequency of clinical pancreatitis was significantly lower in patients given somatostatin (3%) than in those given placebo (10%) (p = 0.03). Conclusions: Prophylactic treatment with somatostatin reduced the frequency of post-ERCP pancreatitis. (Gastrointest Endosc 1999;49:593-8.)