Background: Antiretroviral therapy (ART) has significantly reduced mortality and morbidity of people living with HIV/AIDS (PLWHA); however, the nature of infection and treatment associated with adverse drug reactions often adversely affect patient's health-related quality of life (HRQoL). The purpose of this study was to assess the HRQoL and its associated factors among PLWHA in Ethiopia.Methods: A hospital-based cross-sectional study was conducted among patients taking HAART at Zewditu Memorial General Hospital in Addis Ababa. A face-to-face interview was performed using the HIV/AIDS targeted quality of Life (HAT-QoL) instrument. Patients who met eligibility criteria were approached consecutively while they came to the pharmacy for a medication refill. Descriptive statistics were used to present patient characteristics and HRQoL profiles. Independent t-test and one-way ANOVA were carried out to identify predictors for HRQoL. All statistical tests considered significant at p-value < 0.05.Results: A total of 300 participants were interviewed. The mean age of patients was 41.47 ± 9.45 years and the majority (63.13% ) were females. More than two-thirds (69.7%) of patients were adherents to their medication. The highest HAT-QoL mean score was observed in the overall function domain (84.96±19.87) followed by life satisfaction (83.02±14.61) and physician trust (80.53±20.79). Moderate mean scores were reported in the domains of health worries (71.90±27.00), medication worries (69.44±21.53) and disclosure worries (63.65±30.94) had moderate mean scores, while HIV mastery (56.94±32.52), financial worries (48.81±44.64), and sexual function (12.57±45.56) recorded lower mean scores. Being female, higher educational status, older age, low household income, taking prophylactic therapy, low CD4+ count, and non-adherence were significantly associated with HAT-QoL domains.Conclusions: Overall, HIV/AIDS patients in Addis Ababa had an average level of HRQoL. This study demonstrated that several sociodemographic and clinical variables contribute to reduced HRQoL. Hence, healthcare providers should be paid attention to associated factors that contributed to reduced HRQoL.