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Recent evidence indicates that HIV disproportionately affects ethnic minorities, youth, and women. The present study sought to further understand how sociodemographic and clinical factors impact the health-related quality of life (HRQL) of people living with HIV/AIDS (PLWHA) from the continental United States and Puerto Rico. Two hundred seventy-three participants (87% men, 13% women; 59% Hispanic, 25% black non-Hispanic, 16% white non-Hispanic) completed Spanish or English versions of the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI), an illness-specific measure of HRQL. Univariate and multivariate regression analyses were performed using age, gender, ethnicity, level of education, insurance type, language preference, living arrangement, literacy level, antiretroviral status, CD4+ T cell count, and time since diagnosis as independent variables. Four subscales from the FAHI, physical, emotional, social, and functional/general well-being, were analyzed as dependent variables. Men and Spanish speaking participants reported better physical well-being (p < 0.001). Men also reported better functional well-being (p < 0.05). Participants with a lower CD4+ T cell count, Spanish speakers, and White participants reported better emotional well-being (p < 0.001). Participants who lived with others, had a lower CD4+ T cell count, or were white reported better social well-being (p < 0.001). These results suggest that sociodemographic and clinical factors influence quality of life in PLWHA. Women appear to be particularly vulnerable to adverse quality of life impacts in the physical domains, and ethnic minorities appear vulnerable to adverse impacts in the psychosocial domains.