Background:Substance use among young people is a major public health problem in Iran.Objectives:The aims of the present study were to determine the prevalence of substance misuse and its determinants in medical sciences students in Tehran, Iran.Patients and Methods:A cross-sectional study was performed on a randomly selected sample of 1992 medical sciences students during 2012-2013. Anonymous, structured questionnaires were distributed among the students in each selected class. Substance misuse was defined according to cultural and epidemiological features. Data analysis was performed using chi-squared test, Fisher’s exact test, and binary logistic regression.Results:The prevalence of prescription drug misuse, last year alcohol use, and ever illicit substance use was 4.9%, 6.9%, and 2.9%, respectively. The result of multiple logistic regression model showed that being a male (OR = 4.0), hookah use in the last year (OR = 3.2), prescription drug misuse (OR = 3.2), and alcohol use in the last year (OR = 3.3) were associated with the students’ illicit substance use. Last year alcohol use (OR = 5.3), ever illicit substance use (OR = 3.2), and illicit substance use in friends (OR = 2.6) were associated with prescription drug misuse.Conclusions:Our results suggested that the prevalence of prescription drugs, alcohol and illicit substance use was relatively low, though still significant, among Iranian students, which was strongly associated with family and friends’ use. The findings of this research can be used for planning and evaluating interventions by considering the risk factors and protective factors in Universities.