A randomized prevention design was used to investigate a moderation effect in the association between a polymorphism in the SCL6A4(5HTT) gene at 5-HTTLPR and increases in youths’ risk behavior initiation. Participation in the Strong African American Families (SAAF) program was hypothesized to attenuate the link between 5-HTTLPR status and risk behavior initiation. Youths (N = 641, M age = 11.2 years) were assigned randomly to a SAAF or control condition. Risk behavior initiation across 29 months was linked positively with the 5-HTTLPR genotype and negatively with SAAF participation. Control youths at genetic risk initiated risk behavior at twice the rate of SAAF youths at genetic risk and youths not at genetic risk in either condition.