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The prevalence of clinically significant depressive symptoms is three times higher in people living with HIV than in the general population. Although studies have shown that depression predicts worse course with HIV, few have investigated its relationship with mortality, and none have had a 17-year follow-up period and been conducted entirely during the time since the advent of protease inhibitors.We followed a diverse sample of HIV-positive people (N = 177) in the mid-range of illness for a study on stress and coping. Participants were assessed every 6 months (for 12 years) via blood draw, questionnaires, and interview. Depression was measured using the Beck Depression Inventory. The study began in March 1997 and mortality was assessed in April 2014.In the primary analysis depression, analyzed as a continuous variable, significantly predicted all-cause mortality (hazard ratio = 1.038, 95% confidence interval = 1.008–1.068). With Beck Depression Inventory scores dichotomized, the hazard ratio was 2.044 (95% confidence interval = 1.176–3.550). Furthermore, this result was moderated by race and educational attainment such that depression only predicted worse survival for non-African Americans and those with a college education or higher.Depression is associated with worse long-term survival in people with HIV during 17 years of follow-up. Interventions targeting depression may improve well-being and potentially survival in individuals with HIV. However, since depression did not predict survival in African Americans or those with low education, more research is needed to identify risk factors for long term outcomes in these groups.