Chemsex, defined as the use of psychoactive substances to sustain sexual activity or intensify the experiences associated with it, occurs primarily among men who have sex with men. This article presents the case of a 30-year-old HIV-positive man who engaged in chemsex primarily with mephedrone and, occasionally, GHB, and who subsequently developed mephedrone dependence. He sought psychiatric care because of severe drug craving, recurrent depressive and anxiety symptoms accompanying withdrawal syndromes, and fears of losing control over his addiction. A comprehensive evaluation revealed no co-occurring psychiatric disorders or other clinically significant medical abnormalities apart from known HIV infection, which was effectively controlled with antiretroviral therapy. After initiation of bupropion at a dose of 150 mg per day, improvement in mood, reduction in mephedrone craving, and a marked decrease in the frequency of chemsex were observed. This supports the hypothesis that bupropion-induced stabilization of dopaminergic and noradrenergic neurotransmission may indirectly attenuate craving for stimulants such as mephedrone. Psychotherapy introduced during the course of treatment further supported the patient in pursuing long-term abstinence. To our knowledge, this is the first case report describing successful reduction of drug craving with bupropion in an HIV-positive patient engaging in chemsex without co-occurring psychiatric disorders. This case suggests the potential utility of bupropion in reducing mephedrone craving in individuals engaging in chemsex; however, conclusions drawn from a single clinical observation should be interpreted with caution.