Objective: The purpose of this study was to describe the relationship between viral load and health-related quality of life (HRQOL) in a cohort of persons with human immunodeficiency virus (HIV) infection. Design: We evaluated HRQOL measurements in a clinical cohort of HIV-positive patients recruited from a university-associated HIV primary care clinic. HRQOL instruments included the medical outcomes survey-short form-36(MOS-SF-36) from which mental and physical component summary scores (MCS and PCS) and subscale scores were calculated. Results: Significant negative associations were found between viral load and SF-36 PCS, physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), role-emotional (RE), and vitality (VT). Similar negative associations were found between CD4 cell count and SF-36 summary and subscale scores, with the notable exception of bodily pain. Multivariate analyses controlling for the effects of CD4 cell count and other clinical variables indicated viral load as an independent predictor of SF-36 PCS, RP, BP and VT scores. Conclusions: The relationship between viral load, a measure of HIV disease activity, and several dimensions of the SF-36, a patient-focused measure of HRQOL, appears to be strong and independent of CD4 cell count. These findings suggest that having a lower viral load positively impacts the quality of life of HIV-positive patients.