Evidence for shared heritable influences across domains of substance use suggests that some genetic variants influence broad risk for externalizing behaviors. Theories of externalizing psychopathology also suggest that genetic liability for substance use manifests as temperamental risk factors, particularly those related to behavioral disinhibition, during adolescence. The cholinergic muscarinic receptor 2 gene ("CHRM2") is a promising candidate for studying genetic influences on broad-based risk for externalizing traits. This study examined a candidate "CHRM2" polymorphism (rs1455858) in relation to substance use and personality measures of disinhibition in a sample of high-risk adolescents (n = 124). Bivariate analyses and structural equation modeling (SEM) evaluated associations of rs 1455858 with measures of drug involvement (alcohol, tobacco and marijuana) and disinhibition (indexed by impulsivity and sensation seeking scores). Bivariate analyses showed significant associations of "CHRM2" with several behavioral phenotypes. In SEM analyses "CHRM2" related significantly to latent measures of substance use and disinhibition; additionally, disinhibition mediated the association of "CHRM2" with substance use. These results suggest that "CHRM2" variants are potentially relevant for adolescent substance use and that temperamental risk factors could contribute to these associations.