Previous research demonstrates that carriers of the short allele of the serotonin transporter gene (5-HTTLPR) show both greater susceptibility to depression in response to stressful life events and higher rates of generation of stressful events in response to depression. The current study examines relational security (i.e., self-reported beliefs about attachment security) as a moderator of these effects, building on emerging research suggesting that the short allele acts as a marker of sensitivity to the social environment. Participants were 354 Caucasian adolescents oversampled for maternal depression (137 male, 217 female), assessed at ages 15 and 20. Results indicated that the short allele predicted increased stress generation at age 20 among those with low age 15 security but decreased stress generation among those with high security, and revealed a three-way interaction between age 15 depression, age 15 security, and genotype, where depression predicted stress generation only among short allele carriers with low security. Further, among boys only, security interacted with genotype to predict longitudinal changes in depression diagnosis, with the s-allele predicting relative increases in probability of depression among boys with low security but decreases among boys with high security. Results support the notion of the short allele as a marker of social reactivity, and suggest that attachment security may buffer against the genetic vulnerability introduced by the short allele, in line with predictions of the differential susceptibility theory.