Introduction: The introduction of highly active antiretroviral therapy has relaunched the debate on risky sexual behavior among HIV-infected gay men. It was proposed to study the influences of lifestyle characteristics and health-related quality of life (HRQL) on unsafe sex with casual partners in a representative sample of HIVinfected gay men. Methods: In 2003, a national survey based on face-to-face interviews was conducted among a representative sample of patients selected in a random stratified sample of 102 French hospital departments delivering HIV care. The patients selected for this analysis were gay men who reported having had sex with casual partners during the previous 12 months. Unsafe sex was defined as at least 1 episode of anal sexual intercourse without a condom with a casual partner during the previous 12 months. Health-related quality of life was assessed using the SF-36 Scale. Patients who declared that they had engaged in unsafe sex were compared with those who declared that they had not done so, using the W2 test and logistic regressions. Results: Among the 1117 gay men who participated in the study, 607 declared having had casual partners during the previous 12 months, and 140 (20%) of this latter group had engaged in unsafe sex. Poor mental HRQL was encountered in 68% of the patients and found to be independently associated with unsafe sex, even after multiple adjustment for number of partners, occurrences of binge drinking, use of anxiolytics, use of the Internet, and use of outdoor and commercial venues for sexual encounters. Conclusions: Risky sexual behavior with casual partners is frequent among HIV-infected gay men. In addition to other well-known factors, behavior of this kind was found in this study to be related to poor mental HRQL. A more comprehensive approach to care designed to improve mental quality of life might therefore make for more effective secondary prevention.