Objective: This study tests the efficacy of the Fast Track Program in preventing antisocial behavior and psychiatric disorders among groups varying in initial risk. Method: Schools within four sites (Durham, NC; Nashville, TN; Seattle, WA; and rural central Pennsylvania) were selected as high-risk institutions based on neighborhood crime and poverty levels. After screening 9,594 kindergarteners in these schools, 891 highest risk and moderate-risk children (69% male and 51% African American) were randomly assigned by matched sets of schools to intervention or control conditions. The 10-year intervention (begun in 1991 with three yearly cohorts) included parent behavior-management training, child social-cognitive skills training, reading tutoring, home visiting, mentoring, and a universal classroom curriculum. Outcomes included criterion counts and psychiatric diagnoses after grades 3, 6, and 9 for conduct disorder, oppositional defiant disorder, attention-deficit/hyperactivity disorder, any externalizing disorder, and self-reported antisocial behavior. Grade 9 outcomes were assessed between 2000 and 2003, depending upon cohort. Results: Significant interaction effects between intervention and initial risk level were found at each age but most strongly after grade 9. Assignment to intervention had a significant positive effect in lowering criterion count scores and diagnoses for conduct disorder, attention-deficit/hyperactivity disorder, and any externalizing disorder, and lowering antisocial behavior scores, but only among those at highest risk initially. Conclusions: Prevention of serious antisocial behavior can be efficacious across sex, ethnicity, and urban/rural residence, but screening is essential. (Contains 4 tables.)