The current study examined the effect that students' educational environment has on the prevalence and motivations associated with the misuse of prescription analgesics (MPA). A sample of 893 undergraduate students was recruited from one religiously affiliated private university and one public university in the Southern United States. Participants completed an in-class survey assessing MPA-related behavior and their associated motivations. Results indicated that students attending the religiously affiliated university displayed lower rates of MPA. Multivariate analyses revealed that a positive drug abuse screening, prescription status, and grade point average are the strongest predictors of past-year MPA for both schools. Some motivations for medical misuse differed significantly between campuses. Implications as to how these differences can inform programs aimed at the reduction of prescription analgesic abuse are discussed.