In this article, the authors examine whether delayed substance initiation during adolescence, achieved through universal family-focused interventions conducted in middle school, can reduce problematic substance use during young adulthood. Sixth-grade students enrolled in 33 rural midwestern schools and their families were randomly assigned to 3 experimental conditions. Self-report questionnaires provided data at 7 time points for the Iowa Strengthening Families Program (ISFP), Preparing for the Drug Free Years (PDFY), and control groups through young adulthood. Five young adult substance frequency measures (drunkenness, alcohol-related problems, cigarettes, illicit drugs, and polysubstance use) were modeled as distal outcomes affected by the average level and rate of increase in substance initiation across the adolescent years in latent growth curve analyses. Results show that the models fit the data and that they were robust across outcomes and interventions, with more robust effects found for ISFP. The addition of direct intervention effects on young adult outcomes was not supported, suggesting long-term effects were primarily indirect. Relative reduction rates were calculated to quantify intervention-control differences on the estimated proportion of young adults indicating problematic substance use; they ranged from 19% to 31% for ISFP and from 9% to 16% for PDFY. (Contains 3 footnotes, 4 tables, and 2 figures.)