Introduction: We evaluated the impact of empirical tuberculosis (TB) therapy versus isoniazid preventive therapy (IPT) in addition to antiretroviral therapy (ART) among people living with HIV (PLHIV) on health-related quality of life (HRQoL), assessed changes over time, and examined associations between sociodemographic and clinical factors. Methods: Participants >13 years were enrolled from outpatient clinics in 10 countries. HRQoL was assessed at weeks 0, 8, 24 and 96 with questions about daily activity, hospital or emergency room visits, and general health status. We used logistic regression to examine HRQoL by arm and association with sociodemographic and clinical factors. Results: Among 850 participants (424 empiric arm, 426 IPT arm), HRQoL improved over time with no difference between arms. At baseline and week 24, participants with WHO stage 3 or 4 events, or who had grade 3 or 4 signs/ symptoms, were significantly more likely to report poor HRQoL using the composite of four HRQoL measures. Conclusions: HRQoL improved substantially in both arms during the study period. These findings show that ART, TB screening, and IPT can not only reduce mortality, but also can improve HRQoL in PLHIV with advanced disease.