This study examined whether language preference, as an indicator of acculturation, moderated the effects of a culturally grounded substance use prevention intervention for Mexican and Mexican American middle school students (N = 2,146) in Phoenix, Arizona. The main hypothesis was that levels of program effectiveness would vary based on the language preference of the students and the specific culturally grounded version of the intervention they were assigned. Findings show that matching language preference to particular versions of the intervention did not influence substance use related program outcomes, but that overall program effects (intervention versus control) did vary by language preference. English-language dominant participants, the most at risk sub-group, responded more positively to the intervention, while Spanish dominant, who had low substance use rates at baseline, and bilingual participants did not demonstrate significant differences between the intervention and control groups. Implications for school social work prevention interventions and prevention science in general, are discussed.