Substance use in adulthood compromises work, relationships, and health. Prevention strategies in early adolescence are designed to reduce substance use and progressions to problematic use by adulthood. This report examines the long-term effects of offering Family Check-up (FCU) at multiple time points in secondary education on the progression of substance use from age 11 to 23 years. Participants (N = 998; 472 females) were randomly assigned individuals to intervention or control in Grade 6 and offered a multilevel intervention that included a classroom-based intervention (universal), the FCU (selected), and tailored family management treatment (indicated). Among intervention families, 23% engaged in the selected and indicated levels during middle school. Intention to treat analyses revealed that randomization to the FCU was associated with reduced growth in marijuana use (p < .05), but not alcohol and tobacco use. We also examined whether engagement in the voluntary FCU services moderated the effect of the intervention on substance use progressions using complier average causal effect (CACE) modeling, and found that engagement in the FCU services predicted reductions in alcohol, tobacco, and marijuana use by age 23. In comparing engagers with nonengagers: 70% versus 95% showed signs of alcohol abuse or dependence, 28% versus 61% showed signs of tobacco dependence, and 59% versus 84% showed signs of marijuana abuse or dependence. Family interventions that are embedded within public school systems can reach high-risk students and families and prevent progressions from exploration to problematic substance use through early adulthood. (PsycINFO Database Record