This study examined how ethnic composition and linguistic acculturation within schools affected the efficacy of a youth substance use prevention model program. Data came from a randomized trial of the "keepin' it REAL" program, using a predominantly Mexican American sample of middle school students in Phoenix, Arizona. Schools were randomly assigned to a control group or one of three culturally tailored intervention versions. The authors hypothesized that school ethnic and linguistic acculturation composition (percentage Latino, percentage non-English-speaking at home) and individual level of linguistic acculturation would jointly moderate the efficacy of the prevention program, as indicated by students' alcohol, marijuana, and cigarette use. With multilevel linear modeling and multiple imputation techniques used to manage clustered data and attrition, results show that desired program effects varied by linguistic acculturation level of the school, program version, and individual acculturation level. The Latino intervention version was more efficacious in schools with larger percentages of non-English-speaking families, but only among less linguistically acculturated Latino students. There were no significant school-level program effects connected to the percentage of Latino students at school or the other versions of the program, nor were there any such effects among more linguistically acculturated students.