This study examined the mediated and moderated effects of a universal family-focused preventive intervention, delivered during young adolescence, on internalizing symptoms assessed in young adulthood. Sixth grade students (N = 446; 52% female; 98% White) and their families from 22 rural Midwestern school districts were randomly assigned to the experimental conditions in 1993. Self-report questionnaires were administered at seven time points (pre-test to young adulthood-age 21) to those receiving the Iowa Strengthening Families Program (ISFP) and to the control group. Results showed that growth factors of adolescent internalizing symptoms (grades 6-12) were predicted by ISFP condition and risk status (defined as early substance initiation). Moderation of the condition effect by risk status was found, with higher-risk adolescents benefitting more from the ISFP. Results also supported the hypothesis that the ISFP's effect on internalizing symptoms in young adulthood was mediated through growth factors of adolescents' internalizing symptoms; risk moderation, however, was only marginally significant in young adulthood. The relative reduction rate on clinical or subclinical levels of young adult internalizing symptoms was 28%, indicating that for every 100 young adults displaying clinical or subclinical levels of internalizing symptoms from school districts not offering an intervention, there could be as few as 72 displaying those levels of symptoms in school districts that offered middle school prevention programming. These findings highlight how the positive effects of family-focused universal interventions can extend to non-targeted outcomes and the related potential public-health impact of scaling up these interventions.