Chronic stress and related disruption of hypothalamic-pituitary-adrenal axis reactivity is a known risk factor for depression. Besides its effects on glucocorticoids, stress also impacts the cholinergic system. Therefore, the interaction of two polymorphisms, one on the cholinergic CHRNA4 receptor gene and one on the glucocorticoid receptor gene (NR3C1), on depression was investigated. In a sample of 800 healthy participants, we genotyped for the BCL1 rs41423247 and the CHRNA4 rs1044396 single-nucleotide polymorphisms and assessed depressiveness by means of the Beck Depression Inventory. We identified a significant epistasis effect BCL1 by CHRNA4 showing that carriers of the CC genotype at the BCL1 locus who were also homozygous for the T allele at the CHRNA4 locus had the highest depression scores. This is the first evidence from molecular genetics to show that the hypothalamic-pituitary-adrenal axis and the cholinergic system--both involved in stress reactivity--represent a combined risk factor for depression.