Abstract Background Quality of life (QOL) is one of the major factors to assessing the health and wellbeing of People living with HIV (PLWH). Likewise, improved QOL is among the prominent goals of patient treatment. This study was conducted to investigate the QOL of PLWH in Kermanshah, Iran. Methods This cross-sectional study was conducted on 364 PLWH of Kermanshah between 2016 and 2017. Outpatients were selected as the sample through the convenience sampling method from HIV Positive Clients of Kermanshah Behavioral Diseases Counseling Center. The reasons for the selection of outpatients include: (a) some patients were substance users, homeless or did not have a fixed address to follow-up; (b) addresses and personal details that were registered on the first admission were incorrect or incomplete; (c) due to financial issues, some were forced to relocate frequently and were difficult to track; (d) some patients were convicts or prisoners, making it hard to find them after their release; (e) some of them were from other provinces, where managing access was not easy/possible. Data was collected using WHOQOL-HIV BREF questionnaire (Persian Version). Data also analyzed with STATA 14, and SPSS 23 using T-test and multiple regression. Results This study showed that mean (SD) age of PLWH was 40.21 (10.45) years. Females had better QOL than males except for spirituality, religion and personal beliefs. The gender differences disappeared in multivariate results. A significant association was observed between education and the independence, environment, and spirituality domains of QOL. In addition, being married was correlated with overall QOL, psychological and social relationships domains of QOL of PLWH. Drug use was a behavioral factor with negative influence on the QOL. Conclusion This study found that marital status and drug use were the main predictors of various domains of QOL. Drug use was a behavioral factor with a negative influence on the QOL. Hence, it is recommended that health professionals, planners, and policymakers take effective measures to improve the status quo.