Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic-pituitary-adrenal (HPA) -axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid receptor (GR) sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childhood abuse with rs1360780 in predicting adult depression. 2157 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and Childhood Trauma Questionnaire. The DSM-IV diagnosis of major depressive disorder (MDD) was assessed by interview. Genotypes of rs1360780 were taken from the Affymetrix Human SNP Array 6.0. Significant interaction (p=0.006) of physical abuse with the TT genotype of rs1360780 was found increasing the BDI-II score to 17.4 (95% CI 12.0-22.9) compared with 10.0 (8.2-11.7) in exposed CC/CT carriers. Likewise the adjusted odds ratio (OR) for MDD in exposed TT carriers was 8.2 (95% CI 1.9-35.0) compared with 1.3 (0.8-2.3) in exposed subjects with CC/CT genotypes. Relative Excess Risk due to Interaction (RERI) analyses confirmed a significant additive interaction effect (RERI=6.8; 95% CI: 0.64-33.7; p<0.05). In explorative analyses, the most severe degree of sexual and emotional abuse also yielded significant interaction effects (p<0.05). This study revealed interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression. Given the large effect sizes, rs1360780 could be included into prediction models for depression in individuals exposed to childhood abuse.