The pancreas commonly reacts to endoscopic papillosphincterotomy (EST) with a rise in serum amylase, and acute pancreatitis may also develop. The long-acting somatostatin analogue octreotide has recently been proposed for prevention of colangiopancreatography (ERCP)/EST-induced pancreatic reaction. Therefore, we tested the prophylactic effects of a subcutaneous 3-day administration of octreotide to 60 consecutive patients undergoing ERCP and EST. They were randomly allocated to receive either 200 micrograms octreotide t.i.d. for 3 days (30 cases) or placebo (control group, 30 cases) before the procedure. On the day of the examination, serum amylase levels were determined at baseline and 2, 4, 8, and 24 h thereafter. In the patients as a whole, the increases were statistically significant at 4 h (p < 0.01) and 8 h (p < 0.01). Epigastric pain occurred in 2 patients in the octreotide group and in 13 control subjects (p < 0.001). Even in some patients who had had previous episodes of relapsing pancreatitis, the rise in serum amylase was significantly lower in the octreotide group than in the control group at 4 h (p < 0.01), 8 h (p = 0.05), and 24 h (p = 0.05). Our data suggest that 3 days of prophylactic treatment with octreotide is effective for reducing the rise in serum amylase after EST/ERCP and could be proposed for patients with relapsing pancreatitis and other risk conditions before the Vater's papilla manipulation.