While substance use among teenagers in the United States has declined over the past 6 years, there are still significant ethnic group differences in levels of substance use. The current study examined the effectiveness of a substance use prevention program, "keepin' it REAL,” for 2,146 Mexican and Mexican-American middle school students in Phoenix, AZ, by assessing how variations in acculturation status, as measured through language preference, might influence substance use outcomes. A pretest-posttest experimental design with 3 intervention conditions and 1 control condition was employed to collect self-report data at 2 time periods from students enrolled in 35 public schools in the Phoenix metropolitan area. Results of statistical analyses indicated that acculturation, measured by matching language preferences to particular versions of the intervention, did not affect substance use outcomes following the intervention. However, language preference did impact overall program effects, with English-dominant students responding more positively to the intervention than Spanish-dominant students. Implications for interventions are discussed, including the role school social workers can play as cultural mediators between the majority cultural norms and the culture of origin. Tables, references