Metabolic syndrome (MetS) is a high-risk condition for premature atherosclerotic vascular disease. Patients with MetS display a lipoprotein profile in which dense low-density lipoproteins (LDL), which are more susceptible to oxidation, predominate. Oxidation of lipoproteins can be attenuated in vivo by enzymatic and nonenzymatic antioxidant defenses, but high-density lipoproteins (HDL) play a key role in the protection of LDL from oxidation. Such activity depends on the presence of apolipoproteins (apoA-I, apoA-II, apoA-IV, apoE) and enzymes (paraoxonase 1, platelet activating factor-acetylhydrolase, lecithin:cholesterol acyltransferase, glutathione peroxidase). The impairment of HDL antioxidative activity in MetS is partly related to an enrichment of small HDL in triglycerides and their depletion in cholesteryl esters, to the replacement of apoA-I by serum amyloid A, and to glycation and oxidation of apoA-I. Therapeutic normalization of the quantity and the quality of HDL particles may constitute a novel approach to attenuate atherosclerosis and cardiovascular risk in MetS.