A randomized trial tested the efficacy of three curriculum versions teaching drug resistance strategies, one modeled on Mexican American culture; another modeled on European American and African American culture; and a multicultural version. Self-report data at baseline and 14 months post-intervention were obtained from 3,402 Mexican heritage students in 35 Arizona middle schools, including 11 control sites. Tests for intervention effects used simultaneous regression models, multiple imputation of missing data, and adjustments for random effects. Compared with controls, students in the Latino version reported less overall substance use and marijuana use, stronger intentions to refuse substances, greater confidence they could do so, and lower estimates of substance-using peers. Students in the multicultural version reported less alcohol, marijuana, and overall substance use. Although program effects were confined to the Latino and multicultural versions, tests of their relative efficacy compared with the non-Latino version found no significant differences. Implications for evidence-based practice and prevention program designs are discussed, including the role of school social workers in culturally grounded prevention.