Little is known regarding the impact of hospital-acquired infection (HAI) in acute pancreatitis (AP). We conducted a population-based assessment of the impact of HAI on outcome in AP. Patient data were obtained from the Cardinal Health Clinical Outcomes Research Database, a large population-based data set. Cases with principal diagnosis by International Classification of Diseases, ninth revision, clinical modification 577.0 (AP) between January 2004 and January 2005 were identified. These cases were linked with recently reported HAI data collected by the Pennsylvania Health Care Cost Containment Council. Identification of HAI was based on definitions set forth by the National Nosocomial Infection Surveillance System. We conducted a 5:1 multivariate propensity-matched cohort study to determine the independent contribution of HAI to in-hospital mortality, length of stay (LOS), and hospital charges. From 177 participating hospitals, there were 11,046 AP cases identified. Eighty-two (0.7%) patients developed an HAI. Mortality in the overall AP population was 1.2% vs 11.4% among 405 matched non-HAI controls vs 28.4% among patients who developed HAI (chi(2) test, P < .0001). Fifteen percent of all deaths was associated with an HAI. Both average LOS and hospital charges were significantly increased among patients with HAI compared with matched non-HAI controls. We determined that HAI had a major impact on mortality in AP. Patients who developed HAI also had significantly increased LOS and hospital charges. These differences were not explained by increased disease severity alone. Reducing HAI is an important step to improving outcome in AP.