Sexual contact is the major mode of HIV transmission. Increased sexual risk taking has been described in HIV-infected individuals receiving potent antiretroviral therapy. A new questionnaire on sexual behavior was introduced into the Swiss HIV Cohort Study on April 1, 2000. We evaluated sexual behavior in all individuals who completed the questionnaire for the first time within 1 year after its introduction. Our primary hypothesis was that self-reported unsafe sexual behavior would be more prevalent among individuals with optimal viral suppression. On April 1, 2000, 4948 individuals were registered in the study, and 4723 (95%) completed the questionnaire. Of these individuals, 12% reported unsafe sex, 78% received antiretroviral therapy, and 25% had optimal viral suppression (HIV RNA level always <50 copies/mL during the preceding 12 months). During the preceding 6 months, 55% of individuals had stable and 19% had occasional partners, and 6% had both types of partners. Sexual intercourse was reported by 82% of individuals with stable and 87% of individuals with occasional partners, and of those reporting sexual intercourse in each group, 76% and 86%, respectively, said that they always used condoms. After adjustment for covariates, reported unsafe sex was not associated with optimal viral suppression (odds ratio, 1.04; 95% confidence interval, 0.81-1.33) or antiretroviral therapy (odds ratio, 0.83; 95% confidence interval, 0.65-1.07), but it was associated with gender, age, ethnicity, HIV transmission group, HIV status of partner, having occasional partners, and living alone. There is no evidence that self-reported unsafe sexual behavior is more prevalent among HIV-infected individuals with optimal viral suppression. However, unsafe sex is associated with other factors.