Background: Postoperative outcomes following pancreaticoduodenectomy are well described for pancreatic cancers. Due to a lower incidence rate, complication rates and relative predictive factors are less detailed for ampullary, bile duct and duodenal cancers. Methods: Medical charts of patients operated on between 2001 and 2011 for an ampullary, bile duct or duodenal cancer were reviewed. Data were retrospectively studied with respect to demographics, surgical management, postoperative complications and histological findings. Specific complication rates were reported, and predictive factors for severe morbidity and mortality were determined by multivariate analysis. Results: 135 patients were identified: 55 ampullary, 55 bile duct and 25 duodenal cancers. Twelve patients (8.9%) deceased postoperatively, and 36 others (26.7%) presented severe complications. Sixty-seven percent of the pancreas was soft, and pancreatic hardness was found to be the main protective factor against severe morbidity (HR = 0.36, 95% CI = 0.14-0.94, P = 0.037). Age and postpancreatectomy haemorrhage were independent predictors for death (HR = 14.63, 95% CI = 1.57-135.77, P = 0.018, and HR = 14.71, 95% CI = 2.86-75.62, P = 0.001, respectively). Only the use of an external transanastomotic duct stent significantly reduced both the morbidity (HR = 0.37, 95% CI = 0.16-0.83, P = 0.016), and the mortality (HR = 0.12, 95% CI = 0.02-0.69, P = 0.017). Conclusions: Pancreaticoduodenectomy for ampullary, bile duct and duodenal cancers is a high-risk procedure. The systematic use of transanastomotic duct stents would significantly decrease the complication rate. Older patients should beneficiate from specific preoperative evaluation using an adapted index. Omental flap techniques to prevent a postpancreatectomy haemorrhage should be efficient. Effects of preoperative octreotid to harden the pancreas should be clarified.