This prospective study examined the association between stressful life events and self-reported health in 72 inner-city, low-income African American women with HIV. Depressive symptoms were examined as a potential mediator of this association. Findings indicated that family stressors predicted deterioration in self-reported health status over the 15-month assessment period. Additionally, the association between family stress and self-reported physical health was mediated by depressive symptoms such that the strength of the association between family stress and self-reported health was no longer statistically significant after depressive symptoms were entered in the model. This study suggests a potentially important target for prevention and intervention efforts aimed at enhancing the quality of life of women with HIV.