AbstractThe reported interaction between the length polymorphism (5HTTLPR) in the serotonin transporter gene (SLC6A4) and stressful life events on depression has led to many attempts to replicate but with inconsistent results. This inconsistency may reflect, in part, small sample size and the unknown contribution of the long allele SNP, rs25531. Using a large twin sample of 3,243 individuals from 2,230 families aged 18–95 years (mean = 32.3, SD = 13.6) we investigate the interaction between 5HTTLPR (subtyped with SNP rs25531) and stressful events on risk of depression and suicidality using both ordinal regressions and item response theory analyses. Participants reported via mailed questionnaire (82% response rate) both stressful events in the preceeding 12 months and symptoms of depression. Stressful events were defined as “personal” (affecting the individual), or “network” (affecting close family or friends). One to 10 years later (mean = 4.2 years), participants completed a comprehensive clinical psychiatric telephone interview (83% response rate) which assessed DSM‐IV major depression and ideation of suicidality. Self‐reports of depression and an increase in depression/suicidality assessed by clinical interview are significantly associated with prior personal events (P < 0.001) after controlling for age and sex. However, they are inconsistently associated with prior network events (ranging, ns to P < 0.01) and are not significantly associated with any of the genotype main effects (5HTTLPR, 5HTTLPR + rs25531) or interactions (stress × genotype). We find no evidence to support the hypothesis of any 5HTTLPR genotype by stress interaction. © 2009 Wiley‐Liss, Inc.