BACKGROUND AND AIMS: Reduced high density lipoproteins (HDL) and increased oxidative stress are features of type 2 diabetes. Myeloperoxidase is an oxidative enzyme partly associated with HDL and causing HDL dysfunction. It is an independent risk factor for cardiovascular disease. Paraoxonase-1 is an HDL-associated enzyme that protects against cardiovascular disease and is reduced in diabetes. The present study examined if serum myeloperoxidase was (i) increased in type 2 diabetes, (ii) correlated with paraoxonase-1 activity. METHODS AND RESULTS: The study was based on cross-sectional analyses of serum myeloperoxidase and paraoxonase-1 in type 2 diabetic patients and non-diabetic participants, with and without cardiovascular disease. Serum myeloperoxidase concentrations were not increased in type 2 diabetic patients without cardiovascular disease compared to non-diabetic controls. They were significantly higher in type 2 patients and non-diabetic patients with angiographically confirmed coronary disease. HDL-associated myeloperoxidase was correlated with serum myeloperoxidase (r=0.80, p<0.001) but not HDL-cholesterol (r=0.08) or apolipoprotein AI (r=0.08). Multivariate analyses showed serum myeloperoxidase to be an independent determinant of paraoxonase activities (arylesterase, p=0.024; paraoxonase, p=0.026). CONCLUSIONS: Myeloperoxidase is an independent, negative determinant of paraoxonase-1 activity, which may be one mechanism by which it promotes HDL dysfunction and increases cardiovascular risk. Increased serum myeloperoxidase is not a feature of type 2 diabetes in the absence of overt cardiovascular disease. The level of HDL-associated myeloperoxidase is determined by the serum concentration of the enzyme suggesting that, in the context of reduced HDL concentrations in diabetic patients, myeloperoxidase may have a greater impact on HDL function.