This study was performed to analyze the efficacy of the prophylactic use of octreotide (Novartis, Stein, Switzerland) for pancreatic fistula following a pancreaticoduodenectomy. The medical records of 190 patients who underwent a pancreaticoduodenectomy at the Samsung Medical Center in Seoul, Korea between January 2000 and December 2002 were reviewed. Patients were divided into either the octreotide (n = 81) or control group (n = 109). The octreotide group received subcutaneous injections of 100 microg of octreotide every 12 hours for more than five days after surgery. The control group was not treated with octreotide. The criterion of pancreatic fistula was the drainage of the amylase rich fluid, over 500 U/mL in the three days after surgery. The morbidity and mortality rates were 32.1% and 1.2% in the octreotide group and 31.2% and 0% in the control group, respectively. Pancreatic fistula was the second most common complication (8.4%). In the univariate analysis, octreotide was ineffective in reducing pancreatic fistula (p = 0.26). However, in the multivariate regression analysis, combined gastrectomy (p = 0.018), cellular origin of the disease (p = 0.049), and use of octreotide (p = 0.044) were the risk factors that increased the frequency of pancreatic fistula. Therefore, the routine use of octreotide after a pancreaticoduodenectomy should be avoided until a worldwide consensus is established.