Objective: Since the advent of HAART, the assessment of health-related quality of life (HRQL) has become a major concern in the therapeutic follow-up of people living with HIV. Design: HRQL was evaluated for 2235 participants in the ANRS-EN12-VESPA Study. These participants completed the Medical Outcome Study 36-Item Short Form Health Survey (MOS SF-36) questionnaire. Anxiety and depression were assessed using the Hospital Anxiety and Depression (HAD) scale. Individuals were considered to have an 'acceptable' physical (and mental) HRQL if their MOS SF-36 scores were greater than the 25 th percentile of the corresponding age-sex-specific distribution of scores in the French general population. Methods: Logistic regression models were used to identify factors associated with an 'acceptable' physical and mental HRQL among demographic, psychosocial and clinical characteristics. Potential selection bias caused by non-random missing responses to the MOS SF-36 questionnaire was statistically tested. Results: Physical and mental HRQL were 'acceptable' in 1176 (53%) and 1152 (51%) individuals, respectively. After adjusting for sociodemographic factors, HIV clinical status and hepatitis C co-infection, high HAD scores and the consumption of anxiolytic, antidepressant and hypnotic drugs were found to be negatively associated with normal physical and mental HRQL. Conclusion: The role of disclosure and discrimination is determinant in HRQL, and the various cultural and psychological dimensions require further research. The presence of other infections or co-morbidities requires a comprehensive care system including medical staff and social worker teams. HIV should increasingly be regarded as a chronic disease characterized by different pathological conditions requiring a comprehensive and multidisciplinary approach.