In this study, we examined the relationship between depression and HIV-related risk behavior practices in a sample of 250 at risk, predominantly African American women living in the Atlanta, Georgia metropolitan area. Interviews were conducted between August 1997 and August 2000. Street outreach efforts were used to identify potential study participants, with further expansion of the sample via targeted sampling and ethnographic mapping procedures. Our conceptual model hypothesized a relationship between depression and HIV risk in which depression and condom-related attitudes were construed as intervening (or mediating) variables. A multivariate analysis was used to determine the relationship between depression and women's risk behaviors. The results showed that depression was a key-mediating variable, having its primary influence on women's risky practices through its impact upon their attitudes toward using condoms. Factors associated with depression, included religiosity, closeness of family relationships, financial problems, childhood maltreatment experiences, and drug-related problems. The implications of these findings for prevention and intervention efforts are: (1) heightening faith community involvement and religious participation to decrease depression; (2) working with women whose familial bonds are in need of strengthening to combat depression; (3) providing mental health and counseling services to women who were emotionally and/or sexually abused during their formative years seems to help these women to recover from unresolved issues that may be fueling depression; (4) assisting at risk women who need training in money management issues to minimize their risk for depression; and (5) helping women drug abusers to receive treatment for their drug problems to combat their depression and lower their HIV risk.