In recent years, a considerable body of evidence has emerged regarding the pathogenic role of cortisol in abdominal obesity. The regulation of the corticotropin-releasing hormone (CRH) gene might play an essential role because it is the primary hypothalamic neuropeptide involved in the control of adrenal secretion of cortisol. Therefore, we examined the hypothalamic-pituitary-adrenal function by repeated salivary samples for the assessment of cortisol as well as other endocrine, anthropometric, metabolic, and circulatory variables in middle-aged Swedish men (n = 284). With the restriction enzyme XmnI, a variant in the 5'-flanking region of the CRH gene was identified (T255G). The observed genotype frequencies were 89.9% and 9.7% for T/T and T/G, respectively. Only 1 subject was homozygous for the rare allele (0.4%; G/G). The results showed that the XmnI polymorphism of the CRH gene is not associated with an altered cortisol-secretory pattern or sensitivity to glucocorticoids or with obesity and its related metabolic and circulatory perturbations. However, when the interaction effect between a previously described TthlllI glucocorticoid-receptor gene polymorphism and the present XmnI CRH polymorphism was investigated, the cortisol levels before and during physiologic stress and the total diurnal cortisol secretion were significantly increased among subjects who were carriers for both variants. From these results, we conclude that an abnormal production rate of the CRH gene product in the presence of an inadequate glucocorticoid receptor density might lead to elevated cortisol levels.