Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and increased mortality from cardiovascular disease. CKD results in oxidative stress, inflammation, and high-density lipoprotein (HDL) deficiency, which work in concert to promote atherosclerosis. Normal HDL confers protection against atherosclerosis by inhibiting the oxidation of lipids and lipoproteins and by retrieving surplus cholesterol and phospholipids from lipid-laden cells in the artery wall for disposal in the liver (reverse cholesterol transport). The plasma level of oxidized low-density lipoprotein (LDL) is increased, plasma HDL-cholesterol is reduced, and HDL maturation is impaired in CKD. This study was designed to examine the antioxidant properties of HDL in patients with CKD. In all, 32 stable hemodialysis-dependent patients and 13 age-matched controls were studied. HDL was isolated and used for determination of in vitro antioxidant activity. In addition, the plasma level of key components of HDL, namely paraoxonase (PON), glutathione peroxidase (GPX), platelet activating factor acetylhydrolase (PAF-AH), lecithin cholesterol acyltransferase (LCAT), and apolipoprotein A-I (ApoA-I), were measured. The end-stage renal disease (ESRD) patients exhibited significant reductions of HDL-cholesterol, ApoA-I (-41%), GPX (-50%), and LCAT (-60%) concentrations, and a decrease in PON (-30%) and GPX (-50%) activities. These results were accompanied by a marked reduction of antioxidant activity of HDL (-127%), which was unaffected by the hemodialysis procedure. Thus, in addition to diminished plasma HDL concentration, the composition and antioxidant activity of HDL are altered in CKD; these events can contribute to a heightened risk of atherosclerosis.