Introduction: The quality of life of people with HIV/AIDS has been improved dramatically in the HAART era, the morbidity and the mortality decreasing significantly, however it still remained below the general populations one. Objectives: Global assessment of quality of life in multi-experienced people living with HIV/AIDS and identification of its influencing factors. Methods: The study was conducted on 80 subjects, including 60 multi-experienced patients with HIV/AIDS diagnosed for at least 10 years, monitored by INBI "Prof. Dr. Matei Bals" and 20 subjects with similar age from the general population, without HIV infection. The method of evaluation was composed of structured self-assessment questionnaires on quality of life, pain, fatigue, general symptoms, adherence to antiretroviral therapy and a semi-structured interview. In addition the subjects were evaluated for depression. Between the laboratory tests we retained viral load and immunological status. Results: Using the SF-36 questionnaire and considering a threshold of 80 points for a good quality of life, the number of persons with HIV infection with low quality of life was three times higher than those without HIV infection. (OR = 4.93, p = 0.01). In people with HIV/AIDS, the severity of pain, as well as the severity of fatigue, were correlated with a lower quality of life (p <0.0001). Likewise a low score of quality of life was associated with presence of depression (RR = 2.82, p = 0.0001). In the control group we found only mild pain and the depression was present in one case associated with decreased quality of life. The impact of fatigue was three times higher in people with HIV/AIDS than in the control group. Unlike literature, in our study was found by regression analysis a significant negative correlation between viral load and quality of life score (r = -0.44, r^2 = 0.21, p = 0.0019). Also it was found a correlation between quality of life and CD4 count. Good adherence to treatment was associated with a better quality of life at the same threshold over 80 points on the SF-36 test. (OR = 4.68, p = 0.005). Conclusions: Pain, depression and fatigue are three factors which, in association with the direct effect of HIV, have tremendous impact about quality of life for people living with HIV/AIDS. Besides etiopathogenic treatment, evaluation and correct treatment of these factors can improve the quality of life of patients with HIV/AIDS and can lead to increase adherence to antiretroviral treatment.read more..