Serum paraoxonase 1 (PON1) has been shown to act as an important guardian against cellular damage from oxidized lipids in low-density lipoprotein (LDL), plasma membrane, against toxic agents such as pesticide residues including organophosphates and against bacterial endotoxin. PON1 associated with circulating high-density lipoprotein (HDL) has the ability to prevent the generation of pro inflammatory oxidized phospholipids by reactive oxygen species. The activities of the HDL-associated PON1 and several other anti-inflammatory factors in HDL are in turn negatively regulated by these oxidized lipids. In rabbits, mice, and humans there appears to be an increase in the formation of these oxidized lipids during the acute phase response. This results in the association of acute phase proteins with HDL and inhibition of the HDL-associated PON1 that renders HDL pro inflammatory.In populations, low serum HDL-cholesterol is a risk factor for atherosclerosis and efforts are directed toward therapies to improve the quality and the relative concentrations of LDL and HDL. Apolipoprotein A-I (apoA-I) has been shown to reduce atherosclerotic lesions in laboratory animals. ApoA-I, however, is a large protein that is costly and needs to be administered parenterally. Our group has developed apoA-I mimetic peptides that are much smaller than apoA-I (18 amino acids long vs 243 in ApoA-I itself). These HDL mimetic peptides are much more effective in removing the oxidized phospholipids and other oxidized lipids. They improve LDL and HDL composition and function and reduce lesion formation in animal models of atherogenesis. Following is a brief description of some of the HDL mimetic peptides that can improve HDL and the effect of the peptide on PON1 activity.