Alterations of glucocorticoid receptor sensitivity have been associated with depression. Thus, variation in the glucocorticoid receptor gene that determines glucocorticoid sensitivity may influence risk for depression. In a cross-sectional genetic association study of 526 white outpatients with chronic coronary heart disease, we examined whether haplotypes of the glucocorticoid receptor gene (NR3C1) are associated with depression. Participants were genotyped for four common glucocorticoid receptor gene polymorphisms (ER22/23EK, BclI C/G, N363S, and 9beta A/G) and haplotype analyses were conducted. Depression was assessed by an interview (Computerized Diagnostic Interview Schedule). Of the 526 participants, 355 (67.5%) were non-carriers, 153 (29.1%) had one copy, and 17 (3.2%) had 2 copies of the haplotype 3 allele, which includes the minor allele of the 9beta A/G polymorphism and which has been associated with reduced glucocorticoid sensitivity. The prevalence of depression ranged from 24.4% in the non-carriers to 34.4% in heterozygotes to 52.9% in participants homozygous for the haplotype 3 allele (p<0.01). In logistic regression analyses, carriers of one haplotype 3 allele had an odds ratio of 1.64 (95% CI 1.1-2.5, p=0.02) for depression, while the odds ratio of homozygous haplotype 3 carriers was 3.52 (95% CI 1.3-9.4, p=0.01). These associations persisted after adjusting for potentially confounding variables. A common GR haplotype was associated with depression in a gene-dosage dependent manner and might be a vulnerability factor for depression.