An increasing amount of data suggests that affective disorders are related to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the stress-response system. Corticotropin-releasing hormone receptor-2 (CRHR2)-deficient mice display a stress-sensitive and anxiety-like phenotype suggesting that the CRHR2 is a plausible functional candidate gene influencing the reactivity of the HPA axis and therefore the liability to develop affective disorders. In this study, a gene-based single nucleotide polymorphism (SNP) map of the corticotropin-releasing hormone receptor 2 (CRHR2) was constructed containing one synonymous cSNP in exon 10, two intronic SNPs, and two SNPs in the 5′ upstream regulatory region. No significant difference in allele or genotype frequency was found for four out of the five SNPs between Belgian unipolar (UP) patients and age-, gender-, and ethnicity-matched controls. The cSNP did show allelic and genotypic association with borderline significance (P = 0.04). However, a replication study of this cSNP in a bipolar sample of Belgian origin and a Swedish UP sample did not show significant differences in allele and genotype frequencies. © 2002 Wiley-Liss, Inc.