The study purpose was to determine the factors associated with health-related quality of life (HRQoL) among people living with HIV (PLHIV) in Kazakhstan. A convenience sample of 531 adult PLHIV registered at the Almaty City AIDS Center was used for this cross-sectional study. HRQoL data were collected with the World Health Organization’s Quality of Life HIV brief questionnaire, depression – with Patient Health Questionnaire-9, and clinical data were retrieved from medical records. Multivariate logistic and Tobit censored regressions were used to examine the relationship of socio-demographic, behavioral, and clinical factors with HRQoL and the six specific HRQoL domains: 35.8% of participants did not report good HRQoL. The following variables were identified as independent predictors of poor HRQoL: probable depression (adjusted odds ratio [AOR] 13.42, 95% confidence interval [CI]: 4.56–39.52); history of injecting drug use (AOR 2.10, 95% CI: 1.40–3.14); CD4+ T-cell count <200 cells/mm 3 (AOR 2.17, 95% CI: 1.30–3.62); previously married status (AOR 2.23, 95% CI: 1.16–4.28); and co-infection with tuberculosis, syphilis, toxoplasmosis, Chlamydia, herpes simplex, or cytomegalovirus (AOR 1.59, 95% CI: 1.06–2.39). HRQoL of PLHIV in Almaty was independently influenced by several factors. An interdisciplinary approach is needed in planning healthcare and social services addressing improvement of HRQoL among PLHIV.