Depression is common in people with cardiovascular diseases (CVD) and those with HIV, and is a risk factor for CVD-related mortality. However, little is known about whether HIV influences the relationship between depression and cardiovascular risk. A total of 526 HIV-infected and 132 uninfected women from the Women's Interagency HIV Study were included in an analysis of women who completed twice-yearly study visits over 9.5 years. CVD risk was calculated at baseline and approximately 9.5 years later using the Framingham Risk Score (FRS). Chronic depressive symptoms were defined as Center for Epidemiologic Studies Depression Scale scores of 16 or greater at ≥75% of study visits. Over the follow-up period, 22.8% of HIV-infected women and 15.9% of HIV-uninfected women had chronic depressive symptoms (p=0.08). Baseline FRS was similar between HIV-infected and uninfected women (M=-5.70 ± SE=0.30 vs. M=-6.90 ± SE=0.60, p=0.07) as was follow-up FRS (M=0.82 ± SE=0.30 vs. M=-0.44 ± SE=0.73, p=0.11). Among HIV-infected and HIV-uninfected women, together, follow-up FRS was higher among women with chronic depressive symptoms as compared to those without (M=1.3 ± SE=0.6 vs. M=-0.3 ± SE=0.40, p<0.01), after adjusting for baseline FRS and other covariates. HIV status did not modify the relationship between chronic depressive symptoms and FRS. Chronic depressive symptoms accelerated CVD risk scores to a similar extent in both HIV-infected and-uninfected women. This implies that the diagnosis and treatment of depression may be an important consideration in CV risk reduction in the setting of HIV-infection. The determination of factors that mediate the depression/CVD relationship merits further study.