We analysed sexual difficulties in a nationally representative sample of HIV-infected outpatients in France. Analyses were restricted to the 1,812 HIV-treated participants who reported at least one sexual partner during the 12 months prior to the study. The sample included 40.6% homosexual men and 24.4% women; 68.1% had a steady partner and 48.2% reported casual partners. Sexual difficulties were reported by 33.3% of the selected individuals and were more frequent in those with low sexual activity. Immuno-virological outcomes were not associated with sexual difficulties. After multiple adjustment for sexual frequency and antidepressant consumption, it was found that a larger HIV-network, reporting HIV-discrimination from friends and/or sexual partners, suffering from lipodystrophy and reporting very disturbing HIV-related symptoms were all significantly associated with sexual difficulties. HIV and HIV-treatment experience are associated with sexual difficulties. Psychological support focused on HIV-experience should be tested as a possible tool for improving sexual quality of life.