HYPOTHESIS: Pancreatic fistula (PF), a common and potentially lethal complication of pancreaticoduodenectomy, can be managed nonoperatively in most cases. DESIGN: Retrospective case series. SETTING: Major academic medical and pancreatic surgery center. PATIENTS: A total of 437 consecutive patients who underwent pancreaticoduodenectomy for various diagnoses between January 1, 1988, and August 31, 2004. INTERVENTIONS: Conservative management of PF with an intraoperatively placed closed-suction drain near the pancreaticojejunostomy anastomosis, computed tomography-guided percutaneous drainage, and surgery. MAIN OUTCOME MEASURES: Incidence of PF after pancreaticoduodenectomy and patient outcomes. RESULTS: Fifty-five patients (12.6%) developed a PF, which was most common after resections for ampullary tumors (21.1%) and cystic neoplasms (31.3%), and uncommon after resection for pancreatic cancer (6.5%). The mean number of complications (excluding PF) was greater in the PF group (PF, 1.24; no PF, 0.54; P<.001), but these did not prolong hospital stay (PF, 15.2 days; no PF, 13.7 days; P = .20). Biliary fistula, sepsis, reoperation, and late biliary stricture were more common in patients with PF (P<.05), but mortality rate and long-term survival in patients with either pancreatic or ampullary cancer were unaffected by the presence of PF (P>.40). Fifty-two patients (94.5%) had successful conservative management of their PF with prolonged tube drainage; 4 also required CT-guided percutaneous drainage. Three patients (5.5%) underwent reoperation and 1 died. CONCLUSIONS: Pancreatic fistula is a common problem after pancreaticoduodenectomy. It is associated with increased morbidity, but it does not affect the mortality rate. More than 90% of PF cases can be managed nonoperatively without significantly prolonging hospital stay.