This study tests the impact of an in-school mediated communication campaign based on social marketing principles, in combination with a participatory, community-based media effort, on marijuana, alcohol and tobacco uptake among middle-school students. Eight media treatment and eight control communities throughout the US were randomly assigned to condition. Within both media treatment and media control communities, one school received a research-based prevention curriculum and one school did not, resulting in a crossed, split-plot design. Four waves of longitudinal data were collected over 2 years in each school and were analyzed using generalized linear mixed models to account for clustering effects. Youth in intervention communities (N = 4216) showed fewer users at final post-test for marijuana [odds ratio (OR) = 0.50, P = 0.019], alcohol (OR = 0.40, P = 0.009) and cigarettes (OR = 0.49, P = 0.039), one-tailed. Growth trajectory results were significant for marijuana (P = 0.040), marginal for alcohol (P = 0.051) and non-significant for cigarettes (P = 0.114). Results suggest that an appropriately designed in-school and community-based media effort can reduce youth substance uptake. Effectiveness does not depend on the presence of an in-school prevention curriculum.