Introduction: South Africa has an HIV-infection rate of 5 million people. Between 1995 and 2005, South Africa is expected to have the highest number of AIDS-related deaths on the African continent, a total of 2.7 million. Many infected individuals are women. However, there is very little research conducted with South African women examining the relationship between HIV-infection and psychological distress. Research conducted in the United States indicates that HIV-infection is associated with increased rates of depression and anxiety. This research project aims to explore the relationship between HIV-infection and psychological functioning in the unique socio-political context of South Africa. In addition, the aim is to begin identifying potential factors that moderate this relationship. Method: A group of HIV-infected Black South African women (N = 104) and a community control sample (N = 144) were recruited from both urban and rural areas in the Gautang Province. These women participated in a one-on-one verbally administered interview assessing for psychological distress and various material, personal, family, and social resource factors. Results: HIV-infection was associated with higher rates of depression, but not anxiety. In addition, women with HIV-infection reported more malnutrition risk, emotion-focused coping, stressful life events, powerlessness in relationships with male partners, HIV-stigma, and healthcare satisfaction, than the non-infected women. Variables that were directly associated with depression and anxiety included nutrition, stressful life events, powerlessness in relationships, family social support, and community agency access. HIV-stigma was also directly associated with depression. Furthermore, health-care access, emotion-focused coping, and family social support moderated the relationship between HIV-status and depression, and stressful life events moderated the relationship between HIV-status and anxiety. Discussion: This research study provides further evidence for the relationship between HIV-status and psychological distress among Black South African women. It also identified potential protective factors that could be directly addressed through community-based interventions in order to enhance the psychological functioning of these women.