Background The relationship between hypothalamus/pituitary/adrenal (HPA) axis functioning and (visceral) obesity may be explained by single-nucleotide polymorphisms (SNPs) of the HPA axis. Objective To investigate the relationship between the HPA axis SNP's 'BclI' in the glucocorticoid receptor gene and C8246T in the POMC gene and anthropometric measurements, body composition, 5-h cortisol concentrations, HPA axis feedback sensitivity, as well as HPA axis feedback sensitivity under stress in men and women. Design/subjects/measurements We assessed in 92 men and 102 women (18-55 years, BMI 19-41 kg/m(2) ) anthropometry, body composition using hydrodensitometry and deuterium dilution method, cortisol variability by measuring 5-h cortisol concentrations, HPA axis feedback functioning using a dexamethasone suppression test and HPA axis functioning under a challenged condition consisting of a standardized high intensity test with ingestion of 4 mg dexamethasone. Results In female participants, the 8246C allele carriers compared to the 8246T allele carries were associated with a higher 5-h cortisol exposure (1.52 x 10(5) +/- 0.8 vs 1.18 x 10(5) +/- 0.6 nm.min, P < 0.05) and higher baseline postdexamethasone cortisol concentrations (54.5 +/- 35.6 vs 37.4 +/- 18.5 nm, P < 0.05). In male participants regarding the C8246T allele carriers and in both male and female participants regarding the BclI genotypes, no significant differences in anthropometric measurements, body composition and HPA axis functioning were observed. Multiple regression analysis showed that only increased 5-h cortisol exposure significantly related to changes in anthropometric measurements and body composition; the BclI and C8246T genotypes were not associated. Conclusion Our preliminary data show that in both men and women (18-55 years, BMI 19-41 kg/m(2) ), the SNP's BclI and C8246T of the HPA axis were primarily related to altered HPA axis functioning, rather than to altered anthropometric measurements and body composition.