BACKGROUND:Given the growing interest in the cancer burden in persons living with HIV/AIDS, we examined the validity of data sources for cancer diagnoses (cancer registry versus International Classification of Diseases, Ninth Revision [ICD-9 codes]) and compared the association between HIV status and cancer risk using each data source in the Veterans Aging Cohort Study (VACS), a prospective cohort of HIV-infected and uninfected veterans from 1996 to 2008. METHODS:We reviewed charts to confirm potential incident cancers at four VACS sites. In the entire cohort, we calculated cancer-type-specific age-, sex-, race/ethnicity-, and calendar-period-standardized incidence rates and incidence rate ratios (IRR) (HIV-infected versus uninfected). We calculated standardized incidence ratios (SIR) to compare VACS and Surveillance, Epidemiology, and End Results rates. RESULTS:Compared to chart review, both Veterans Affairs Central Cancer Registry (VACCR) and ICD-9 diagnoses had approximately 90% sensitivity; however, VACCR had higher positive predictive value (96% versus 63%). There were 6,010 VACCR and 13,386 ICD-9 incident cancers among 116,072 veterans. Although ICD-9 rates tended to be double VACCR rates, most IRRs were in the same direction and of similar magnitude, regardless of data source. Using either source, all cancers combined, most viral-infection-related cancers, lung cancer, melanoma, and leukemia had significantly elevated IRRs. Using ICD-9, eight additional IRRs were significantly elevated, most likely due to false positive diagnoses. Most ICD-9 SIRs were significantly elevated and all were higher than the corresponding VACCR SIR. CONCLUSIONS:ICD-9 may be used with caution for estimating IRRs, but should be avoided when estimating incidence or SIRs. Elevated cancer risk based on VACCR diagnoses among HIV-infected veterans was consistent with other studies.