To evaluate the relationship between employment status and health-related quality of life (HRQOL) in HIV/AIDS. A total of 361 participants provided baseline data in the context of an ongoing cohort study examining the natural history of neurobehavioral functioning and its effects on HRQOL. We administered tests and collected laboratory data to determine demographic status, HIV disease markers, psychosocial symptom burden, neurocognitive function and HRQOL (MOS-HIV). We performed regression analyses to evaluate the contribution of employment status to the physical and mental health components of quality of life (QOL). Multivariate analyses showed that employment status was strongly related to better physical and mental health QOL after controlling for potential confounders. We found, however, that employment status had a greater impact on physical health than mental health QOL [physical health (β = 6.8, 95% CI 4.6 to 9.1) and mental health QOL (β = 3.3, 95% CI 0.93 to 5.7)]. The effect of employment for physical health QOL was stronger than that observed for ethnicity, social support, or having an AIDS diagnosis and was comparable to that observed with having many HIV-related symptoms. This cross-sectional study suggests that there may be physical and mental health benefits associated with obtaining or keeping employment, or more likely that both selection and causation mechanisms comprise an interactional and reinforcing process.