The pathogenesis of atherosclerosis is mediated by genetic susceptibility along with a variety of cardiovascular risk factors and environment influences. As atherosclerotic lesions progress, they manifest several features typical of chronic inflammation, such as the presence of monocyte/macrophages, T-cells and inflammatory cytokines. This inflammatory response is fueled and enhanced by oxidative stress, which may be the link between lipid disorders and inflammation. Oxidation of lipoproteins is intimately involved in all stages of atherosclerosis and oxidative byproducts co-localize with inflammatory cells. When low density lipoprotein enters the subintimal space, it is oxidized by several mechanisms, including both enzymatic and non-enzymatic pathways and becomes a ligand for scavenger receptors on macrophages leading to generation of foam cells. Oxidized LDL is not only pro-inflammatory and pro-atherogenic, but several of the neoepitopes generated during oxidation are highly immunogenic and result in the generation of autoantibodies. Autoantibodies to OxLDL are found within atherosclerotic lesions and in apparently healthy subjects, as well as patients with various manifestations of cardiovascular disease. In this article, the role of circulating autoantibodies to OxLDL in cardiovascular disease will be reviewed. Although controversy still exists, the overall evidence supports the notion that IgG autoantibodies to OxLDL are associated with pro-atherogenic properties and IgM autoantibodies to OxLDL with atheroprotective properties. Whether such antibodies have a modulating role or are merely reflectors of atherogenesis has not been fully determined. Data is also emerging on the role of natural antibodies, which are primarily of the IgM class, that recognize oxidation-specific epitopes. Among other properties, these antibodies may be involved in housekeeping functions in binding and clearing pro-inflammatory oxidized lipids and therefore may be atheroprotective. Several studies have also recently evaluated the potential therapeutic role of antibodies to OxLDL either through active immunization using OxLDL or model oxidation-specific epitopes as immunogens or through passive immunization with human antibodies directed to oxidation-specific epitopes. Although these investigation are at an early stage, they show promise that immune modulation may lead to novel approaches to treat atherosclerosis and cardiovascular disease.