Among patients undergoing maintenance hemodialysis, a decreased high-density lipoprotein cholesterol (HDL-C) concentration is among the most common abnormalities of lipid metabolism and apparently is an independent risk factor for vascular disease. A common missense mutation of cholesteryl ester transfer protein gene, D442G (Asp 442 to Gly), increases HDL-C levels through the reduced activity of cholesteryl ester transfer from HDL to VLDL, but the mutation also may lead to reduced activity of reverse cholesterol transport. To investigate the effect of the D442G polymorphism on atherosclerotic complications in dialysis patients, the genotype and allele frequency of the polymorphism were determined in 414 unselected dialysis patients and 220 control subjects, and postprandial serum lipid levels were measured in the dialysis patients. A similar genotype distribution was found between hemodialysis patients and healthy control subjects, and in dialysis patients with and without vascular disease. Serum levels of total cholesterol and HDL-C did not differ between patients with and without the mutation and in patients with and without vascular disease. However, patients with sub-median HDL-C levels (<45 mg/dl) had an independent odds ratio of 1.8 for vascular disease (95% confidence interval, 1.04 to 3.2; P < 0.05). In this low-HDL-C subgroup, patients with the D442G mutation had a significantly higher prevalence of vascular disease than those with no mutation (54.5% versus 24.4%; P < 0.05), and an independent odds ratio of 4.9 (95% confidence interval, 1.05 to 22.65; P < 0.05). In conclusion, the D442G mutation is an independent risk factor for atherosclerotic complications in dialysis patients with HDL-C levels below 45 mg/dl.