Background:Substance use among college students in Iran is a serious problem. Determining the pattern of substance use among University students is an important issue for implementing prevention and treatment programs.Objectives:The present survey attempts to determine the prevalence of substance usage and associated risk factors among the students of Jahrom University of Medical Sciences and Islamic Azad University of Jahrom, Jahrom, Iran.Patients and Methods:This cross-sectional study was carried out from December 2012 to February 2013 and included 1149 randomly selected students of two Jahrom universities. A standard questionnaire was used for data gathering. Data were analyzed using the SPSS version 15 for Windows. T-test and Chi-square T-test and Chi-square and Logestic regression tests were used for data analysis.Results:Tobacco (28.3%), alcohol (13.0%), and cannabis and marijuana (5.2%) were the most common substances used by the students. The prevalence of substance use among the male students was significantly higher (OR: 1.5, 95%CI: 1.42 - 2.68, P < 0.001). The risk of at least single episode of substance usage was higher among the students which were living alone (OR: 3.03, 95%CI: 1.74 - 5.28, P < 0.001) The most important motivators for beginning substance use were curiosity, in 46.4%, and seeking pleasure, in 28.8%.Conclusions:Substance usage is considered as a risk factor for students’ health among University students in Iran. Design of educational courses addressing the detrimental effects and dire consequences of substance usage could help to improve control programs. Universities could improve their drug abuse control programs by focusing on the high risk groups determined by relevant studies.