ABSTRACT Objective This study aimed to investigate the prevalence of lifetime, last year, and last month use of illicit drugs and associated factors among the first to fourth-year students at the Tehran University of Medical Sciences in Iran. Method Sampling method was multi-stage cluster sampling. Anonymous self-administered questionnaires were distributed to 1050 students. We provided prevalence of lifetime, last 12 months, last month, and daily use for the main classes of drugs. Using the bivariate and multivariate logistic regression model, we evaluated correlated factors of any drug use in the past 12 months. Results Overall, 945 students participated in this study. A total of 6.6% reported any illicit drug use in the past 12 months (11.2% among males vs. 3.1% among females) Cannabis was the most used drug in the past year, reported by 4.9% of the participants, followed by methylphenidate (2.9%). There was an association between illicit drug use in the past 12 months with smoking cigarettes and using alcohol in the past 12 months and drug use among friends or family members. Conclusions The prevalence of drug use among the students at Tehran University of Medical Sciences has increased compared to similar previous studies, which call for preventive measures.