Metabolic syndrome is a constellation of major risk factors for cardiovascular disease. In affected individuals with this syndrome, the independent contribution of low high-density lipoprotein-cholesterol and increased triglyceride levels to the development of atherosclerosis remains to be clarified. We assessed the relationship between these 2 parameters and several surrogate markers for atherosclerosis. One hundred and twenty overweight cases, defined as having high-density lipoprotein-cholesterol (<or=25 age- and gender-specific percentile in general population) and high triglyceride values (>or=75 percentile) were compared with 120 discordant overweight controls defined on lipid values (high-density lipoprotein-cholesterol >or=50 percentile and triglycerides <or=50 percentile). Case-control pairs were matched for age and gender. Carotid and femoral arteries were examined to determine carotid intima-media thickness and the presence of atherosclerotic plaque(s). Endothelial function was assessed by laser Doppler flowmetry in the skin microvasculature. Daytime ambulatory blood pressure monitoring was performed for each subject. Cases had higher prevalence of atherosclerotic plaques (mean 1.50 +/- 0.15 vs 0.80 +/- 0.15, P < .001), increased carotid intima-media thickness (mean 0.66 +/- 0.15 vs 0.61 +/- 0.15, P < .01), and a significantly reduced temperature-induced and postischemic endothelial vasodilation compared with controls. In conclusion, low high-density lipoprotein-cholesterol and high triglycerides levels are major contributors to peripheral atherosclerosis and are associated with an increase in intima-media thickness and impaired microvascular endothelial function in overweight individuals.