The aim of this study is to define the risk factors that predict adverse outcomes for patients undergoing pancreaticoduodenectomy for periampullary cancer in the Department of Veterans Affairs Healthcare System (VA). The VA National Surgical Quality Improvement Program prospectively collected data on 462 patients undergoing pancreaticoduodenectomy in 123 VA medical centers from 1990 to 2000. Independent variables included 68 preoperative and 12 intraoperative variables. The main outcome measures were 30-day postoperative mortality and morbidity, as measured by a set of 20 pre-defined complications. Predictive models for 30-day morbidity and mortality were constructed using logistic regression analysis. The 30-day morbidity rate was 45.9% (212/462). The 30-day postoperative mortality rate was 9.3% (43/462). Significant predictors of mortality included: preoperative serum albumin, American Society of Anesthesiologists classification, preoperative bilirubin >20mg/dl, and operative time. The use of preoperative biliary tract instrumentation did not predict postoperative death or septic complications. This study provides a set of preoperative risk factors that are predictive of adverse outcome following pancreaticoduodenectomy. These factors may assist in patient selection for this procedure and are likely to facilitate risk-adjusted comparison of pancreaticoduodenectomy outcomes between different health care systems.