This cross-sectional study evaluated the quality of life and its associated factors among people living with HIV/AIDS at a regional reference center for the treatment of HIV/AIDS in southern Brazil. WHOQOL-HIV Bref, ASSIST 2.0, HAD Scale, and a questionnaire were used to assess 625 participants on quality of life, clinical and sociodemographic characteristics, drug use, depression and anxiety. Multivariate analysis was performed through linear regression. The lowest results for quality of life were associated with being female, age (< 47 years), low education levels, low socioeconomic class, unemployment, not having a stable relationship, signs of anxiety and depression, abuse or addiction of psychoactive substances, lack of perceived social support, never taking antiretroviral medication, lipodystrophy, comorbidities, HIV related hospitalizations and a CD4+ cell count less than 350. Psychosocial factors should be included in the physical and clinical evaluation given their strong association with quality of life domains.