Objective: In an era of highly active antiretroviral therapies, the authors needed to confirm previous findings showing that stress and depression have an impact on HIV disease progression. The goal of the current study was to examine the effects of lifetime trauma, recent stressful events, and depression on all-cause and AIDS-related mortality among HIV-infected men and women. The authors hypothesized that these psychosocial variables would predict significantly faster HIV-specific and all-cause mortality. Method: The authors consecutively sampled HIV-infected men and women who received care at one of eight infectious diseases clinics in five Southeastern states. The sample included 490 patients who were followed by interview for 27 months and followed with their medical records for up to 41 months. Results: There were 29 deaths; 16 were AIDS-related. More lifetime trauma and antigenic marker on helper/inducer T cells (CD4) <200 significantly predicted faster all-cause and AIDS-related mortality. For those at or above the median in trauma, the all-cause death rate was 3.54 per 100 person-years, compared to 1.72 for those below the median. For those at or above the median in trauma, the AIDS-related death rate was 2.13 per 100 person-years, compared to 0.77 for those below the median. Depressive symptoms and higher baseline viral load were significantly related to greater risk of AIDS-related mortality. Conclusions: Further research is needed to determine if interventions to address trauma and depression can modify these detrimental effects on HIV.