Research has identified children of alcoholics (COAs) as a population at increased risk for developing substance use problems. Genetic studies support the Al allele of the D2 dopamine receptor gene (DRD2) as a risk marker for alcoholism and substance use disorders. In this study, substance use was assessed in 48 adolescent boys of alcoholics with the DRDR A1(+) allele (A1A1/A1A2 genotypes) or the A1(-) allele (A2A2 genotype). The results revealed that boys with the A1(+) allele tried (p=0.0001) and got intoxicated on alcohol more often (p=0.009) than boys with the A1(-) allele. Boys with the A1(+) allele tried more (p=0.004) and used more substances overall (p=0.008) than boys with the A1(-) allele. Boys with the A1(+) allele developed a tobacco habit more often (p=0.03) and experienced marijuana high at an earlier age (p=0.001) than boys with the A1(-) allele. The best predictors of substance use severity in boys with the A1(+) allele were Psychoticism (p=0.01) and Negative Affect (p=0.04). The results provide support for the DRD2 A1 allele as a marker identifying a subgroup of COAs at high risk for developing substance use problems.