Objective: Antiretroviral therapy (ART) affords longevity to patients infected with the human immune deficiency virus (HIV). Since little is known about the health-related quality of life (HRQoL) of persons who have been on ART for at least five years, the present study investigated the HRQoL of these patients in Botswana. Method: Medical records, structured interviews, and the World Health Organization Quality of Life-BREF (WHOQoL-HIV-BREF) instrument were employed to obtain information from 456 respondents. Results: Univariate and multivariate regression analyses showed that respondents' highest scores were in the physical domain (mean = 15.8, SD = 3.5), while the lowest scores were in the environment domain (mean = 12.9, SD = 2.5). Thus, the physical domain had the greatest impact on patients' overall HRQoL. Self-education about HIV-related issues was significantly correlated with all domains of HRQoL scores: physical ( = -2.32, CI95% = -3.02, -1.61); psychological ( = -2.26, CI95% = -2.87, -1.65); independence ( = -1.81, CI95% = -2.54, -1.06); social relationships ( = -1.40, CI95% = -2.13, -0.67); environment ( = -1.58, CI95% = -2.13, -1.04); and spirituality ( = -1.70, CI95% = -82.27, -1.13). Significance of results: HRQoL assessments can identify and address patients' needs, and it is important that guidelines be developed that will yield improved care to ART patients in Botswana.