Most studies on chemsex focus on the health risks associated with the practice, whereas less attention has been paid to the perception of sexual gratification in men who have sex with men (MSM) who use these substances. The purpose of this study was to explore the effects of chemsex substances on sexual response, motivations to engage in chemsex and the relationship with sober sex. Thirty-one Italian cisgender MSM involved in sexualized drug use were interviewed and transcripts were thematically analyzed. An ad hoc grid exploring sociodemographic data, chemsex sexual experience, motives, and relationships with sober sex was used during telephone-based interviews. Participants showed significant individual differences in how chems may affect their sexual experience. The most reported effects were an increase in sexual desire and subjective arousal, access to higher disinhibition, possible erection and ejaculation difficulties, significant extension of the sexual experience duration, and an intensified perception of intimacy and pleasure. All the positive outcomes of substances on sex creates a great curiosity around chemsex, which is among the primary motives to engage in chemsex for the first time. Over time, other motives may emerge, also connected to substance abuse and craving. Some men reported to be motivated by their partners and friends and to use chemsex to cope with depressive mood/anxiety symptoms, stress and sexual problems. Many differences were reported between chemsex and sober sex. Chemsex seems to embody the idea of transgressive and exciting sex, while sober sex is outlined as a more intimate encounter, that can be significantly affected by performance anxiety. These results offer some new perspectives that may add interesting information to the literature and be fundamental for future prevention and harm-reduction projects. Although this study is based on a small group of Italian MSM and the interviews were not audio-recorded, transcripts were consistent with scientific literature that considers it important to pay attention to the positive links between sex and substance use. The promotion of safer sexual behavior should contemplate an in-depth discussion and recognition of both pleasurable and distressing aspects of chemsex sexual experience, its motivations over time and perceived differences with sober sex. Nimbi FM, Rosati F, Esposito RM, et al. Sex in Chemsex: Sexual Response, Motivations, and Sober Sex in a Group of Italian Men Who Have Sex With Men With Sexualized Drug Use. J Sex Med 2021;18:1955-1969.