In the face of rising rates of substance use among Mexican youth and rapidly narrowing gender differences in use, substance use prevention is an increasingly urgent priority for Mexico. Prevention interventions have been implemented in Mexico but few have been rigorously evaluated for effectiveness. This article presents the long term effects of a Mexico-based pilot study to test the feasibility of a linguistically specific (Mexican Spanish) adapted version of keepin’ it REAL, a school-based substance abuse prevention model program. University affiliated researchers from Mexico and the US collaborated on the study design, program implementation, data collection, and analysis. Students and their teachers from two middle schools (secundarias) in Guadalajara participated in this field trial of Mantente REAL (translated to Spanish). The schools were randomly assigned to treatment and control conditions. The sample of 431 students reported last 30 day substance use at three times (one pretest and two posttests). Changes in substance use behaviors over time were examined using growth curve models. Long term desired intervention effects were found for alcohol and marijuana use but not for cigarettes. The intervention effects were greater for girls than for boys in slowing the typical developmental increase over time in alcohol use. Marijuana effects were based on small numbers of users and indicate a need for larger scale studies. These findings suggest that keepin’ it REAL is a promising foundation for cultural program adaptation efforts to create efficacious school-based universal prevention interventions for middle school students in Mexico.