Background: Rates of obesity have risen disproportionately for ethnic minority youth in the United States. School-based programs may be the most comprehensive and cost-effective way to implement primary prevention in children. In this study we evaluated the effect of a school-based obesity prevention on the outcome of body mass index percentile (BMI%), with baseline weight class and ethnicity examined as moderators. Methods: Participants (N = 125), ages 7-11 (56% female) from 4 urban, low-income, ethnic minority (58% black, 42% Latino) schools were recruited. Two schools received the Urban Initiatives Work to Play health intervention, and 2 demographically matched schools served as wait-list controls. Results: Hierarchical multiple regression was used to analyze the independent and interactive effects of key variables on BMI%. An interaction between intervention status and ethnicity revealed Latino youth in the intervention had lower BMI% than those in the control group. Participation did not cause BMI% outcomes to decrease for black participants. Conclusions: The study demonstrates the intervention is effective, but that the effectiveness varies across ethnicity. Interventions can be made more efficient and cost-effective by targeting youth of a common ethnicity that has shown empirical responsiveness to certain program elements.