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Aims/hypothesis: Elevated oxidative stress, hyperglycaemia, and dyslipidaemia involving low levels of HDL particles are key proatherogenic factors in type 2 diabetes mellitus. We examined the relationship of oxidative stress, and the degree of glycaemia and triglyceridaemia, to antioxidative function of HDL particle subspecies in type 2 diabetes. Subjects and methods: Five H DL sub- fractions (2b, 2a, 3a, 3b, 3c) were isolated by density gradient ultracentrifugation from well-controlled type 2 diabetic subjects (n=20) and normolipidaemic, non-diabetic controls (n=10). Specific antioxidative activity (capacity to protect LDL from oxidation on a unit particle mass or on a particle number basis), chemical composition and enzymatic activities were measured in each subfraction. Systemic oxidative stress was assessed as plasma levels of 8-isoprostanes. Results: Specific antioxidative activity of small dense HDL3b and 3c particles in diabetic patients was significantly diminished (up to -47%, on a particle mass or particle number basis) as compared with controls. Plasma 8- isoprostanes were markedly elevated (2.9-fold) in diabetic patients, were negatively correlated with both specific anti- oxidative activity of HDL3 subfractions and plasma HDL cholesterol (HDL-C) levels, and were positively correlated with glycaemia and triglyceridaemia. Paraoxonase 1 activity was consistently lower in diabetic HDL subfractions and was positively correlated with HDL3 antioxidative activity. The altered chemical composition of diabetic HDL3 sub- fractions (core cholesteryl ester depletion, triglyceride enrichment) was equally correlated with diminished antioxidative activity. Conclusions/interpretation: Antioxidative activity of small dense HDL is deficient in type 2 diabetes, is intimately linked to oxidative stress, glycaemia and hypertriglyceridaemia and primarily reflects abnormal intrinsic physicochemical properties of HDL particles. [ABSTRACT FROM AUTHOR]