Background Highly Active Antiretroviral Therapy (HAART) is a standard of HIV management to suppress viral load and delay progression to AIDS. However, questions have been raised about the use of antiretroviral therapy and how it affects quality of life (QoL) of people living with HIV/ AIDS (PLWHA). The study hence aimed to assess the QoL of PLWHA who were taking HAART at Mizan-Tepi University Teaching Hospital (MTUTH) and identify factors associated with QoL. Methods A cross sectional study was conducted among PLWHA receiving HAART at MTUTH from March 04-April 1, 2018. Patients were recruited consecutively and interviewed with structured questionnaire. A data abstraction tool was used to extract data from patient medical records. Quality of life was assessed using the World Health Organization Quality of Life HIV-BREF (WHOQOL-HIV-BREF) standard tool. Data was entered to Epi-Info version 3.5.3 and analyzed using SPSS version 22 for windows. A multivariable logistic regression analysis was fitted to identify factors associated with QoL. A statistical significance was established at a p value <0.05. Results A total of 240 participants with the mean age of 35.11 (SD = 9.08) years were included in the study. This study found that 57.1% of the patients had high global score of QoL. Patients with normal current health (AOR = 3.38, 95% CI = 1.56-7.31)) and having family support (AOR = 3.12, 95% CI = 1.51-6.46) were positively associated with high global score of QoL, while patients with low HAART adherence (AOR = 0.40, 95%, CI = 0.19-0.86) were negatively associated with high global score of QoL.