Background: A major issue to consider in high risk behaviors such as substance abuse is personality factors. Objectives: This study aimed to determine the role of personality factors (anxiety sensitivity, sensation seeking, hopelessness, and impulsivity) in substance use, psychotropic drug use, smoking, and alcohol drinking in a sample of male medical students in Iran. Patients and Methods: In this cross-sectional study, conducted in Isfahan and Kermanshah Medical Universities in Iran, a total of 425 male medical students were randomly selected with the proportional to size from different faculties to participate voluntarily in the study. A self-report written questionnaire was applied to collect data. Then, the obtained data were analyzed by SPSS version 20 using logistic regression statistical tests at 95% significant level. Results: Our findings showed that hopelessness (OR = 1.095, 95% CI: 1.033, 1.160) and sensation seeking (OR = 1.139, 95% CI: 1.065, 1.219) were the main influential predictors on smoking. Anxiety sensitivity (OR = 1.436, 95% CI: 1.114, 1.851) and impulsively (OR = 1.443, 95% CI: 1.153, 1.806) were the main influential predictors on drug abuse. In addition, anxiety sensitivity (OR = 1.460, 95% CI: 1.004, 2.124) and sensation seeking (OR = 1.756, 95% CI: 1.120, 2.753) were the main influential predictors on psychotropic drug abuse. Finally, sensation seeking (OR = 1.222, 95% CI: 1.121, 1.331) was the main influential predictor on alcohol drinking. Conclusions: Our findings indicated that sensation seeking was the best predictor for alcohol drinking, cigarette smoking, and psychotropic drug abuse.