Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Västmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R²=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression.