To test the hypothesis that low HDL-C concentration interferes with vascular endothelial function and lipoprotein oxidation, we measured endothelium-dependent flow mediated dilatation (FMD, %) of the brachial artery in young men (n=20) classified prospectively into two groups on basis of having either low or high HDL-C concentration over the past 2 years. As an estimate of in vivo low-density lipoprotein oxidation (ox-LDL), we measured LDL diene conjugation. FMD was present in the group with high HDL-C concentration, but impaired in the group with low HDL-C (5.5+/-3.2 vs 0.2+/-1.2%, P<0. 001). The group with high HDL-C level had significantly lower levels of ox-LDL compared to low HDL-C group (18.0+/-1.8 vs 22.9+/-4.4, P</=0.01). In all subjects, FMD correlated with HDL-C (r=0.59, P=0. 006), HDL(2)-C (r=0.62, P=0.004) and ox-LDL (r=-0.56, P=0.013) but not with HDL(3)-C (r=0.16, P=0.52). We conclude that constantly low HDL-C concentration is related with endothelial dysfunction and increased oxidative stress in healthy young men, consistent with the idea that HDL particles may protect endothelium and inhibit the oxidation of LDL. These findings may offer insight into increased atherosclerosis associated with low HDL-C levels.