Early onset of substance use among adolescents has been found to be associated with later risky sexual behaviors. This study examined long-term follow-up data from a large randomized school-based drug prevention trial to (1) investigate the long-term impact of the prevention program on drug use and sexual behaviors that put one at elevated risk for HIV infection; and (2) use growth modeling procedures to examine potential mechanisms of intervention effects. Self-report survey data were collected from students in the 7th grade, prior to the intervention in 1985, and in grades 8, 9, 10, and 12. Participants in the intervention condition received a 30-session drug prevention program in 7th through 9th grades. Follow-up surveys were completed by 2042 young adults (mean age = 24) in 1998. As young adults, participants were considered to be engaging in high-risk behavior for HIV infection if they reported having multiple sex partners, having intercourse when drunk or very high, and recent high-risk substance use. The intervention had a direct protective effect on HIV risk behavior in the overall sample in young adulthood. Furthermore, among participants receiving 60% or more of the prevention program, analyses showed that the intervention significantly reduced growth in alcohol and marijuana intoxication over the course of adolescence, which in turn was associated with a reduction in later HIV risk behavior. The behavioral effects of competence-enhancement drug prevention programs can extend to risk behaviors including those that put one at risk for HIV infection.