Objective: Eight percent of college students report past year prescription stimulant misuse (nonmedical use of stimulants defined as taking stimulants in a manner other than prescribed). Despite this high prevalence rate, primary prevention efforts are lacking on college campuses. Participants and Methods: A prescription stimulant misuse primary prevention intervention targeting first-year college students was developed, refined, and pilot tested. Existing substance use treatment (motivational interviewing) and time management (cognitive behavioral therapy for adult ADHD) techniques were integrated into the novel brief prevention intervention. Focus groups provided feedback to help refine the prevention intervention. Following refinements, 484 first-year college students were randomly assigned to condition (327 treatment, 157 control) and followed for 3 months. Results: Participants rated the intervention as satisfactory. After controlling for time invariant covariates, condition significantly predicted prescription stimulant misuse. There was a lower rate of past 3-month prescription stimulant misuse reported in the intervention group (4.9%) compared to the control group (11.5%). Academic expectancies remained stable in the intervention group yet increased in the control condition over time. Time management skill ratings remained stable in both groups. Changes in academic expectancies, yet not time management skills, were a partial mediator of the prevention efficacy in prescription stimulant misuse at 3-month follow-up. Conclusions: These results provide preliminary support for the acceptability and efficacy of a brief primary prevention intervention for college student prescription stimulant misuse. Changes in positive prescription stimulant expectancies, yet not time management skills, appear to be potential targets for future preventive efforts.