OBJECTIVES: HIV-related stigma (HRS) is rooted in the sociocultural constructions associated with infectious diseases, particularly in the HIV/AIDS epidemic. The purpose of this study was to determine the level and impact of HRS in a culturally diverse sample of persons attending an urban HIV clinic. METHODS: Using a combination of quantitative (n=87) and qualitative (n= 27) methods, this study examined the level of HIV-related stigma in four domains: personalized, disclosure-related, negative self-image, and public attitudes. Relationships between HRS, depressive symptoms, and quality of life were explored. Interviews were used to identify sources of HRS and processes utilized to manage HRS. RESULTS: HRS is a significant problem for persons living with HIV/AIDS. Persons with higher levels of HRS are more likely to experience depressive symptomatology and a lower quality of life than persons who perceive less stigma. CONCLUSIONS: HIV-positive persons experience various forms of stigma in meeting family, societal, and cultural expectations. Nursing interventions can reduce HRS and promote coping as well as connectedness to family, community, and the health care system.