This cross-sectional study, based on an anonymous questionnaire, describes the use of psychoactive substances (PAS) among individuals visiting the Free Centers for Information, Screening, and Diagnosis of Sexually Transmitted Infections (CeGIDD) in the Languedoc-Roussillon region in 2014, their characteristics and risky sexual behaviors, as well as their perception of the risk of HIV infection. Of the 5,368 participants, with a median age of 24, 56% were men—including 19% of men who have sex with men (MSM)—and 44% were women, of whom 6% were lesbian or bisexual. Individuals who had previously used psychoactive substances accounted for 53% of the participants, with cannabis being the most common, but stimulants (cocaine) and hallucinogens were also used at a significant frequency; 7% of users consumed at least three psychoactive substances. Using multiple correspondence analysis and ascending hierarchical clustering, seven user profiles were identified, including notably a profile of student users and experimenters of cannabis, cocaine, poppers, and hallucinogens; a profile of poly-users of PAS used in a sexual context, comprising a high proportion of young MSM and young bisexual women; and a profile of older users, who used heroin significantly. While sexual risk-taking associated with psychoactive substances and alcohol is common, the perception of sexual risk is low and shows little variation among different psychoactive substance users, with the exception of MSM, who perceive themselves to be at greater risk. These findings support the need for prevention strategies tailored to users’ behaviors, delivered during screening, with the aim of simultaneously reducing sexual risks and risks associated with psychoactive substance use.