This study tested for gender differences in the impact of linguistic acculturation on pro-drug norms, substance use intentions, and actual substance use among youth of Mexican heritage in a large metropolitan area in the Southwest United States. The authors analyzed baseline survey data provided by 2,487 middle school students of Mexican heritage who were part of a larger, multiethnic randomized efficacy trial of a drug abuse prevention program. Using multi-group structural equation modeling, the authors found that linguistic acculturation was positively and directly related to adherence to pro-drug norms, substance use intentions, and recent alcohol use, controlling for age, poor grades, and socioeconomic status. In addition, linguistic acculturation had an indirect effect on substance use intentions and recent alcohol use through pro-drug norms. The direct effect of linguistic acculturation on pro-drug norms was stronger for girls than for boys, as was its indirect effect on substance use intentions.