Macrophage cholesterol accumulation and foam cell formation is the hallmark of early atherogenesis. In addition to macrophages, at least three more major players regulate atherosclerosis development; paraoxonase 1 (PON1), antioxidants, and HDL. PON1 is an HDL-associated lactonase which posses antioxidant and anti-atherogenic properties. PON1 protects against macrophage-mediated LDL oxidation, and increases HDL binding to macrophages which, in turn, stimulates HDL's ability to promote cholesterol efflux. These two major anti-atherogenic properties of HDL (and of PON1) require, at least in part, macrophage binding sites for HDL-associated PON1. Indeed, PON1, as well as HDL-associated PON1, specifically binds to macrophages, leading to anti-atherogenic effects. Macrophage PON1 binding sites may thus be a target for future cardioprotection therapy. Studying the interactions among PON1, antioxidants, and macrophages can thus assist in achieving appropriate treatment and prevention of atherosclerosis.