We examined the relationship of several cardiovascular disease (CVD) risk factors to flow-mediated vasodilatation of the brachial artery (FMD) and the clustering effect of risk factors on FMD in Japanese subjects free of CVD. In 819 Japanese subjects free of CVD (age 45+/-10 years, 611 men and 208 women), FMD correlated significantly with the Framingham risk points score (FRS) (r=-0.27, p<0.01). FMD was higher in subjects in the 1st tertile of the FRS range than in patients in either the 2nd or 3rd tertiles of the FRS range, but it was similar between the subjects in the 2nd and 3rd tertiles. FMD was found to have a significant independent negative correlation with age (beta=-0.19, p<0.01), gender (beta=-0.024, p<0.01) and smoking habit (beta=-0.08, p=0.02). In subjects >or=50 years of age, the FMD in men with one CVD risk factor, excluding smoking, was similar to that in men with no CVD risk factors. CVD risk factors did not attenuate FMD in women. Thus, in Japanese subjects free of CVD, FMD may be a useful marker of CVD risk, but it may not be a robust marker for endothelial damage related to clusters of CVD risk factors. Age, gender and smoking were independent variables related to the impairment of FMD, which therefore appears to be less applicable in subjects aged 50 or more, and especially in women. (Hypertens Res 2008; 31: 2019-2025).