OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of hepatopancreaticoduodenectomy (HPD) for patients with biliary cancer. BACKGROUND: HPD is thought to be the only curative treatment for widespread bile duct cancer and for some advanced cases of gallbladder cancer; however, HPD has not yet been accepted as a standard operative procedure because of concerns over morbidity and mortality. METHODS: Fifty-two patients undergoing HPD were retrospectively reviewed. The patient and tumor characteristics, preoperative treatments, operative results, and survival outcomes were investigated. RESULTS: Preoperative biliary drainage and portal vein embolization were applied for all patients undergoing right-sided HPD or a left trisectionectomy. A major hepatectomy was performed in 42 patients, and a 2-stage pancreaticojejunostomy was selected in all the cases. The 90-day mortality was 0; however, 1 patient died because of a liver abscess 230 days after surgery. Postoperative significant complications (grade III or greater) and liver insufficiency were observed in 19 (37%) and 2 (3.8%) patients, respectively, and no abdominal bleeding events after the formation of a pancreatic fistula were encountered. The 5-year overall survival rate was 44.5%, and a significant difference was not observed between patients with bile duct cancer and those with gallbladder cancer. The operative procedure was switched to an HPD in 13 patients based on intraoperative findings, and the recurrence-free survival rate for these patients was poorer than that for patients who did not require a switch in operative procedure (P = 0.004). CONCLUSIONS: HPD can be safely performed using the presently reported surgical strategies with acceptable short and long-term outcomes. A precise assessment of the extent of tumor spread might improve patient outcome.