Background/Aims The study compared illegal drug and alcohol use behaviors between medical and nonmedical users of prescription opioids (PO) and nonmedical users with distinct motives to use. Method An ethically-approved cross-sectional study (2010) was conducted on a representative sample of private university students (n=570), using a self-filled anonymous questionnaire. Results About 25% reported using PO only medically and 15% nonmedically. The prevalence of alcohol and illegal drug use was consistently higher among nonmedical than medical PO users. Adjusting for age and gender, lifetime medical users of PO were more likely to use marijuana only (OR=1.8, 95%CI= 1.1, 2.8), while nonmedical users were at higher odds of using marijuana, ecstasy, cocaine/crack, and alcohol problematically. Compared to non-users, students who took PO nonmedically for non-therapeutic reasons were more likely to use various illegal drugs, but nonmedical users who took PO to relieve pain/help in sleep were only more likely to use marijuana (OR=2.5, 95%CI=1.1, 5.4) and alcohol (e.g., alcohol abuse, OR=3.8, 95%CI= 1.4, 10.1). Conclusion Youth who use PO nonmedically to self-treat have a different alcohol and illegal drug-using profile than those who take it for non-therapeutic reasons.