OBJECTIVES: To understand the relationship between socio-demographic variables, clinical factors, highly active anti-retroviral therapy (HAART) and health related quality of life (QoL) in HIV-infected individuals participants in the IANUA multicenter study. METHODS: Data relating to patients with HIV infection admitted to 3 infectious disease units in Genoa (Italy) between 2012 and 2014 are collected and analyzed. Univariate and multivariate association of demographic and clinical factors with QoL (computed using EQ-5D-3L) are examined. QoL determinants are assessed using a tobit model, while a logistic model is implemented in order to investigate the relation between specific patients characteristics and the likelihood of having higher QoL. RESULTS: Results of the empirical modeling suggest that being Italian and having a job are positively associated with QoL, whereas being a female, taking other drugs in addition to anti-retroviral drugs and being subsidisied are negatively related to QoL. Among clinical factors, last CD4 cell count level cannot be considered as significant predictor of QoL, while higher QoL seem to be defined by single tablet regimens. CONCLUSIONS: The study investigates the major determinants of QoL among HIV patients and the results provide some informative tools useful to improve strategies aiming at maximizing QoL. As monitoring of QoL is nowadays a priority for clinicians, further work will be based on “dynamic” analysis comparing QoL at the initial time and QoL at 6-months follow up.