Anxiety sensitivity (AS) is a dispositional characteristic that predisposes to the development of anxiety disorders (eg, panic and post-traumatic stress disorder) and major depression. AS is subject to genetic and environmental influences, the former as yet unidentified and the latter known to include childhood maltreatment. The serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR) has been associated with depression, but most consistently in the context of environmental stress. We tested the hypothesis that 5-HTTLPR genotype and childhood maltreatment would interact to increase susceptibility to AS in young adults. Subjects were European-American college undergraduates (N=150, median age 18 years) characterized on a measures of AS (Anxiety Sensitivity Index) and retrospective childhood maltreatment (Childhood Trauma Questionnaire [CTQ]). 5-HTTLPR genotypes were obtained from blood-derived DNA. Linear regression was used to model relationships between 5-HTTLPR, childhood emotional abuse, and AS; covariates such as sex, neuroticism, and ancestral proportion scores were incorporated into some models in a larger, ethnically heterogenous sample (N=247) to evaluate robustness of the findings to model assumptions. A statistically signficant interaction was observed between levels of childhood emotional (or physical) maltreatment and 5-HTTLPR genotype. Specifically, S/S individuals with higher levels of maltreatment had significantly higher levels of AS than subjects in other groups. No such relationship was found for neuroticism, attesting to the possible specificity of the findings for AS. Findings were consistently robust to the inclusion of covariates, and were not confounded by population stratification. In conclusion, these results provide evidence of a specific genetic influence on anxiety sensitivity-an intermediate phenotype for anxiety (and depressive) disorders; this effect is modified by severity of childhood maltreatment. These findings are consistent with the notion that 5-HTTLPR operates broadly to moderate emotional responsivity to stress.