Objective: Although prior recent research has revealed a significant relationship between the nonmedical use of prescription drugs, demographic characteristics, college-specific risk factors, and other substance use among college students, there remains a need to conduct a comparative analysis on the differential impact these factors may have on predicting nonmedical prescription drug use. Participants and Methods: In 2008 a convenience sample of 599 undergraduate students attending a southeastern university completed a self-report survey measuring substance use behaviors. Results: Males, Greeks, and freshman were more likely than females, non-Greeks, and upperclassman to use nonmedical prescription drugs in the past year. Multivariate analyses, however, indicate that the excessive use of alcohol and other illicit drugs are more influential than demographic and college-specific risk factors. Conclusion: Poly-drug use was found to be the most significant predictor of the use of nonmedical prescription drugs as compared to demographic and college-specific risk factors. (Contains 3 tables.)