BACKGROUND: Approximately 1.7 million individuals per year are affected with health care-associated infections (HAIs) in the United States. The authors examined trends in the incidence of HAI after major cancer surgery (MCS) and risk factors for HAI to describe the effects of HAI on mortality after MCS. METHODS: Patients undergoing 1 of 8 MCS procedures within the Nationwide Inpatient Sample between 1999 and 2009 were identified (n ¼ 2,502,686). Generalized linear regression models were used to estimate the impact of the primary predictors (procedure type, age, sex, race, insurance status, Charlson comorbidity index, hospital volume, and hospital bed size) on the odds of HAI and in-hospital mortality. Trends in incidence were evaluated with linear regression. RESULTS: Overall, MCS-associated HAI incidence increased 2.7% per year (P < .001), whereas mortality decreased 1.3% per year (P < .001). (OR, 8.66; 95% CI,. CONCLUSIONS: Between 1999 and 2009, the incidence of MCS-associated HAI events increased; however, HAI-associated mortality decreased. That said, significant disparities exist in the hospital and demographic attributes associated with MCS-associated HAI, with attendant health policy implications. Moreover, HAI remains detrimentally linked to mortality during hospitalization.