Background: A relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported. Aims: To replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism. Method: At the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression. Results: No relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype. Conclusions: The 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.