The metabolic syndrome, a worldwide health problem, represents a cluster of metabolic abnormalities that are well established risk factors of cardiovascular disease. There is increasing evidence that physiological variations in glucocorticoid (GC) action could contribute to the development of these risk factors. Disturbances of the hypothalamic-pituitary-adrenal (HPA) axis might underlie the metabolic syndrome and its association with obesity and insulin resistance. In the present study we evaluated the sensibility to GC, in a series of patients with metabolic syndrome, compared to healthy individuals. Forty patients with metabolic syndrome (24 female, 16 male, 24-71 years old) were included in this study. The negative feedback action of GCs on the HPA axis was evaluated in vivo through salivary (SC) and plasma (PC) cortisol levels determined pre- and post 0.25, 0.5 and 1mg of dexamethasone (DEX) given at 11:00 pm. Forty healthy individuals previously studied were also submitted to the DEX tests. Wilcoxon rank-sum test and Wilcoxon matched pairs signed rank sum test were used when appropriate. Data are shown as mean±SEM. In patients with metabolic syndrome the administration of increasing doses of DEX (0.25, 0.5 and 1.0 mg) resulted in a dose-dependent increase in mean circulating DEX levels (0.24 ± 0.03; 0.40 ± 0.04 and 0.90 ± 0.08 nmol/L) and a dose-dependent decrease of plasma cortisol (208.3 ± 23.0; 83.8 ± 18.4 and 44.9 ± 7.1 nmol/L) and salivary cortisol (19.4 ±2.7; 5.0 ± 1.4 and 2.1 ± 0.3 nmol/L). No significant difference of plasma and salivary cortisol levels (basal and post DEX) was observed between healthy individuals and patients with metabolic syndrome. Using plasma and salivary cortisol levels of <50 nmol/L and <2.6 nmol/L, respectively, as criteria of HPA axis suppression, patients with metabolic syndrome showed PC (79.5%) and SC (82.0%) suppression post 1.0 mg; 62.% (PC) and 65.0% (SC) post 0.5 mg and 5.0% (PC) and 5.0% (SC) post 0.25 mg of DEX. Patients with metabolic syndrome showed a tendency of lower cortisol DEX suppression compared to controls. In conclusion, the present data suggest that decreased sensitivity to GC feedback is more prevalent in metabolic syndrome patients, confirming that the HPA axis is activated in this condition. These results give support to the emerging concept that disruption of feedback regulation of the HPA axis might be involved in the pathogenesis of metabolic syndrome.