Compared to patients not receiving treatment, antiretroviral therapy users may experience a lower viral load, an increased CD4 count, slower disease progression, fewer opportunistic infections, and more rapid recovery time from HIV-related illnesses. As such, health-related quality of life is likely to be considerably greater for antiretroviral therapy users than for patients not receiving treatment. The dearth of quality of life research in sub-Saharan Africa brings into focus the need for and importance of documenting the various dimensions of well-being among people living with HIV. We administered the Functional Assessment of HIV Infection to a convenience sample of patients receiving antiretroviral therapy in the Western Cape in South Africa. We used confirmatory factor analysis and exploratory factor analysis to determine the factor structure of the Functional Assessment of HIV Infection. The confirmatory factor analysis revealed a poor model fit of the data. However, the exploratory factor analysis factor structure closely approximated the subscales of the measure, indicating the dimensions of physical, emotional, functional, and social well-being and cognitive functioning. We identified problematic items on the Functional Assessment of HIV Infection contributing to the poor model fit and argue that the measure is potentially useful in assessing quality of life among antiretroviral therapy users in South Africa.