Antisocial personality disorder (ASPD) frequently co-occurs with substance dependence (SD). A functional polymorphism (5-HTTLPR) in the serotonin transporter gene has been widely studied as a risk factor for a variety of psychopathologic conditions including aggressive/violent behavior. Childhood abuse is an important predictor of ASPD. We examined 5-HTTLPR genotype and adverse childhood events (ACEs) as risk factors for ASPD in a SD sample.Study participants [602 European-Americans (EAs) and 779 African-Americans (AAs)] were interviewed to obtain lifetime diagnoses of ASPD and SD and information on ACEs. Triallelic genotypes for 5-HTTLPR were obtained using standard methods. We used logistic generalized estimating equations regression to examine ACEs and 5-HTTLPR genotype and their interaction as predictors of ASPD, separately by population group.There were 203 (14.7%) participants diagnosed with ASPD. The frequency of the low-activity 5-HTTLPR S' allele did not differ by ASPD diagnosis, and there was no overall 5-HTTLPR×ACE interaction. However, among European-Americans, male sex (odds ratio=3.36; P<0.001) and ACE history (odds ratio=1.47; P=0.002) were significant predictors of ASPD. Among AAs, there was a significant interaction of sex×5-HTTLPR genotype×ACEs (χ=13.92, P<0.001). Among AA men, each additional ACE significantly increased the odds of ASPD irrespective of genotype, whereas among AA women, the effect of ACEs on ASPD was significant only among S' homozygotes. However, these results are limited by the small sample size in each subgroup, (particularly AA women with S'S' genotype; N=7) and require replication.Childhood maltreatment contributes to the risk of ASPD, an effect for which there is preliminary evidence of moderation by 5-HTTLPR genotype in AA women.