Age-related decline of plasma dehydroepiandrosterone-sulfate (DHEA-S) levels may be associated with the risk of cardiovascular disease in women. We investigated whether plasma DHEA-S levels are related to endothelial function in postmenopausal women with coronary risk factors. One hundred and fifteen postmenopausal women (mean age+/-SD: 57+/-5 years; range: 48-65 years) who underwent measurement of flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography were enrolled. Plasma hormone levels were determined in the morning after a 14-h fast, and the relationship between hormone levels and FMD was analyzed. DHEA-S was significantly correlated with %FMD (r=0.392, p<0.001), while estradiol, total testosterone and cortisol were not. %FMD in the highest quartile of DHEA-S was 1.8-fold higher than that in the lowest quartile (5.3+/-1.3 vs. 2.9+/-2.0 [means+/-SD], p<0.01). Multiple regression analysis revealed that DHEA-S was related to %FMD independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus and smoking (beta=0.344, p<0.01), and was itself independent of age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and smoking (beta=0.291, p<0.05). In conclusion, plasma DHEA-S levels were weakly but significantly related to endothelial function in postmenopausal women independent of other coronary risk factors, suggesting a protective effect of DHEA on the endothelium.