A prospective, randomized, controlled trial was performed to determine the efficacy of somatostatin in the prevention of pancreatic stump-related complications with elimination of surgeon-related factors in high-risk patients undergoing pancreaticoduodenectomy. From August 1997 to December 2000, 54 patients, 28 men and 26 women, with age ranged from 32 to 89 years, were randomly assigned to somatostatin group ( n = 27) or placebo group ( n = 27). Ninety-four percent of the patients had pancreatic and periampullary lesions; 6% had secondary lesion involving the duodenum such as local recurrent colon carcinoma and renal cell carcinoma. These patients received either standard pancreaticoduodenectomy or pylorus-preserving pancreaticoduodenectomy. An experienced surgeon performed all operations in same fashion to minimize the surgical factor. A transanastomotic tube was inserted into the pancreatic duct for diversion of pancreatic juice in the pancreaticojejunostomy for a 3-weeks period postoperatively. Intravenous infusion of somatostatin was given at a dose of 250 microg/hr in the somastotatin group and normal saline was given to the control group for 7 days postoperatively. There was one perioperative death in each group, resulting in a 3.7% mortality rate. In the somastotatin group, as compared to the placebo group, the incidence of overall morbidity and pancreatic stump related complications were significantly lower with a mean decrease of 50% pancreatic juice output and a slightly shorter duration of hospital stays. In conclusion, after excluding surgeon related factor, prophylactic use of somatostatin reduces the incidence and severity of pancreatic stump related complications in high-risk patients having pancreaticoduodenectomy via decreased secretion of pancreatic exocrine.