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Background—Investigations of gene-environment interaction (G × E) in depression have implicated a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress-depression relationship. However, recent evidence for 5-HTTLPR G × E in depression has been inconsistent. The present study examined the moderating effect of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene on the strength of 5-HTTLPR G × E. Methods—A community sample of youth (n = 384) was genotyped for 5-HTTLPR and COMT. A multi-method, multi-informant index of chronic family stress was derived from interviews and questionnaires administered at youth age 15. G × G × E was examined in relation to depression diagnoses between ages 15 and 20 and depressive symptoms at age 20. Results—Significant three-way interactions were observed for both depressive symptoms and diagnoses, such that 5-HTTLPR G × E occurred only in the context of COMT val158 allele homozygosity. For val158 homozygotes, the 5-HTTLPR L allele exerted a protective effect in the face of stress. No genetic main effect or two-way G × E was found for 5-HTTLPR