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Background: Psychological stress is associated with unhealthy lifestyles, including smoking. Moreover, religiousbeliefs can play a significant role in relieving mental disorders such as anxiety and stress. Due to the frequentexposure of medical students to stressful situations, this study was conducted with the aim to investigate therelationship of internal and external religious orientation with perceived stress and nicotine dependence.Methods: This correlational study was carried out on medical students of Kerman University of MedicalSciences, Kerman, Iran, in 2015. The sample size was determined to be 224 individuals using the Morgantable. The participants were selected using stratified random sampling. The data collection tools consisted ofa demographic information form, the Religious Orientation Scale (ROS) (Allport and Ross), the PerceivedStress Scale (PSS-14), and the Fagerstrom Test for Nicotine Dependence (FTND). Data were analyzed usingmultiple regression analysis, analysis of variance (ANOVA), Pearson correlation coefficient, and t-test inSPSS software.Findings: The findings of the study showed that internal religious orientation had a significant negativerelationship with perceived stress and nicotine dependence; however, no significant relationship wasobserved between external religious orientation and these variables.Conclusion: Based on the results of the study, it can be concluded that the religious beliefs of individuals havea preventive role in perceived stress and nicotine dependence.