OBJECTIVE:: Despite the success of antiretroviral therapy (ART), excess mortality continues for those with HIV infection. A comprehensive approach to risk assessment, addressing multi-organ system injury on ART, is needed. We sought to develop and validate a practical and generalizable mortality risk index for HIV-infected individuals on ART. DESIGN AND METHODS:: The Veterans Aging Cohort Study (VACS) was used to develop the VACS Index, based on age, CD4 count, HIV-1 RNA, hemoglobin, AST, ALT, platelets, creatinine and Hepatitis C status, and a Restricted Index based on age, CD4 count and HIV-1 RNA with an outcome of death up to six years after ART initiation. Validation was in six independent cohorts participating in the ART Cohort Collaboration (ART-CC). RESULTS:: In both the development (4932 patients, 656 deaths) and validation cohorts (3146 patients, 86 deaths) the VACS Index had better discrimination than the Restricted Index (c-statistics 0.78 and 0.72 in VACS, 0.82 and 0.78 in ART-CC). The VACS Index also demonstrated better discrimination than the Restricted Index for HIV deaths and non-HIV deaths, in men and women, those younger and older than 50 years, with and without detectable HIV-1 RNA, and with or without HCV co-infection. CONCLUSIONS:: Among HIV-infected patients treated with ART, the VACS Index more accurately discriminates mortality risk than traditional HIV markers and age alone. By accounting for multi-organ system injury, the VACS Index may prove a useful tool in clinical care and research.