Objective: A longitudinal, prospective design was used to investigate a moderation effect in the association between early adolescent substance use and risky sexual behavior 2 years later. A genetic vulnerability factor, a variable nucleotide repeat polymorphism (VNTR) in the promoter region of the serotonin transporter gene SLC6A4, known as 5-HTTLPR, was hypothesized to moderate the link between substance use at age 14 and risky sexual behavior at age 16. This VNTR has been associated with risk-taking behavior. Design: African American youths in rural Georgia (N = 185) provided 2 waves of data on their substance use and sexual behavior. Genetic data were obtained via saliva samples. Main Outcome Measures: Substance use and sexual risk behavior were assessed using youth self-report items developed for this investigation. Results: Multiple regression analyses indicated that the presence of 1 or 2 copies of the short allele of the VNTR interacted with substance use to predict sexual behavior. Substance use had little effect on sexual behavior for youths without the short allele; this effect was greatly increased for youths with the short allele. Conclusion: Genetic vulnerability affected the implications of early onset substance use for later sexual behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)