This paper reports on the evaluation of a culturally grounded prevention intervention targeting substance use among urban middle-school students. The curriculum consists of 10 lessons promoting antidrug norms and teaching resistance and other social skills, reinforced by booster activities and a media campaign. Three versions were delivered: Mexican American, combined African American and European American, and Multicultural. Thirty-five middle schools were randomly assigned to 1 of the 3 versions or the control. Students completed baseline and follow-up questionnaires over a 2-year period (total 6,035 respondents). Analyses utilizing a generalized estimating equations approach assessed the overall effectiveness of cultural grounding and the cultural matching hypothesis. Support was found for the intervention's overall effectiveness, with statistically significant effects on gateway drug use as well as norms, attitudes, and resistance strategies but with little support for the cultural matching hypothesis. Specific contrasts found the Mexican American and Multicultural versions impacted the most outcomes.