This study assesses the degree to which culturally specific interventions enhance substance abuse prevention effectiveness for targeted cultural groups. A large and diverse (African American, Hispanic, American Indian, and Asian) sample of 10,500 youth across 48 programs was obtained. Youth participating in culturally specific programming showed greater program satisfaction and felt programs were more personally meaningful than youth in non-culturally specific programs. Culturally specific programs for African American youth were also more effective in preventing substance use. This finding may be attributable to the fact that Africentric programs apply a comprehensive and structured approach to substance abuse prevention and that cultural messages are clearly linked to important protective factors. (Contains 4 tables and 1 figure.)