Alcohol problems are influenced by both genetic and environmental factors. Evidence from twin models and measured gene-environment interaction studies has demonstrated that the importance of genetic influences changes as a function of the environment. Research has also shown that family-centered interventions may protect genetically susceptible youth from developing substance use problems. In this study, we brought large-scale gene identification findings into an intervention study to examine gene-by-intervention effects. Using genome-wide polygenic scores derived from an independent genome-wide association study of adult alcohol dependence, we examined whether an adolescent family-centered intervention would moderate the effect of genetic risk for alcohol dependence on lifetime alcohol dependence in young adulthood, approximately 15 years after the start of intervention, among European American (N = 271; 48.3% in the intervention condition) and African American individuals (N = 192; 51.6% in the intervention condition). We found that among European American individuals, the intervention moderated the association between alcohol dependence polygenic scores and lifetime alcohol dependence diagnosis in young adulthood. Among participants in the control condition, higher alcohol dependence polygenic scores were associated with a greater likelihood of receiving an alcohol dependence diagnosis; in contrast, among participants in the intervention condition, there was no association between alcohol dependence polygenic scores and alcohol dependence diagnosis. No moderation effect was found among African Americans. These results demonstrate that modifying environments of genetically vulnerable youth could reduce the likelihood of developing alcohol dependence and underscore the significance of environmentally focused prevention and intervention efforts.