Postoperative hemorrhage (PH) after duodenopancreatectomy (DP) is frequently lethal. The aim of this study was to delineate guidelines of management. Between August 1994 and July 2003, 172 patients underwent DP for cancer. Altogether, 26 patients were subjected to an institutional protocol (IP) with standard-dose chemoradiation (CRT) and 4 patients to an extrainstitutional protocol (EIP) with high-dose CRT. Sixteen patients (9.3%) were reoperated for PH. Hemorrhage occurred in 23% of irradiated patients (4 EIP, 3 IP) and in 6% of nonirradiated patients [confidence interval (CI) 1.8-6.5]. Pancreatic leak occurred in nine patients with PH (56%). Sentinel bleeding (SB) was noted in eight patients (50%) with a mean delay of 10 days after DP. Overall mortality after hemorrhage was 56%. Morality rates of patients with EIP or IP were, respectively, 100% and 0%. Mortality rates of patients with or without SB were similar. Mortality rates of axial bleeding (hepatic artery, mesenteric vessels) or lateral bleeding (pancreas remnant, splenic vessels) were, respectively, 88% and 25% (CI 1.6-8.6). Completion of pancreatectomy was achieved in 75% without rebleeding. Preoperative high-dose CRT increased the risk of fatal PH. Because SB occurs before massive hemorrhage, prompt reoperation could reduce mortality. Completion of pancreatectomy was essential during reintervention. Axial bleeding supports high mortality. Moving to the left, the pancreatojejunostomy could avoid contact of pancreatic juice with axial vessels in the case of pancreatic leakage. Ligating the gastroduodenal artery during DP had to leave a stump of around 1 cm to facilitate hemorrhage control without ligating the common hepatic artery.