Since the beginning of the epidemic, people living with HIV and the social groups to which they belong have been stigmatized worldwide. This cross-sectional study, conducted between July and November 2003, investigated the association between HIV stigma and mental health status among black women living with HIV in the Western Cape province of South Africa. Eligible participants completed a questionnaire that assessed HIV stigma, sociodemographic, and mental health status measures. Participants were recruited from one of five primary health care clinics in the rural Western Cape. Recruiters screened 177 women to assess their eligibility. Of those screened, 68% (n = 120) were eligible because they were black South Africans, between the ages of 18 and 45, were living with HIV/AIDS, sought primary health care from one of the five study clinics, spoke Xhosa, and provided written informed consent. A priori hypotheses postulated that women reporting more HIV stigma would experience more consequences for mental health sequelae. The main outcome measures were mental health status variables, including depressive symptomatology, stress of HIV discrimination, quality of life, post-traumatic stress, suicidal ideation and fear of HIV disclosure. In linear regression models, more reports of HIV stigma were associated with significantly more depressive symptomatology (P = 0.03) and a lower quality of life (P = 0.00). The findings from this study indicate that HIV stigma is associated with adverse mental health sequelae among black Xhosa women living with HIV. Educational and legal efforts are required to reduce HIV stigma. Moreover, a public health infrastructure that integrates HIV/AIDS treatment and mental health services may be a promising strategy for reducing the adverse mental health consequences of HIV stigma.