Atherosclerosis is a multifactorial vascular disorder responsible for the highest rate of mortality in the western world. During the last decades, research on this disease has primarily focused on the role of lipids, which are essential to the formation of lesions in the vascular intima that ultimately leads to clinically apparent atherosclerotic plaques. More recently, several anecdotal findings have indicated the possible involvement of the immune system in the process of atherogenesis. In particular, the appearance of immunocompetent cells as well as humoral antibodies in the intima in the early stages of disease development supports the view of an inflammatory component in this disorder. In addition to the search for lipid-associated antigens that might entail full-blown atherosclerosis, other candidate antigens capable of inducing an immune response in the vascular wall have also been explored. Within the probable group of antigens for immune responsiveness, heat shock protein (hsp) 60/65 became a serious candidate, upon observation that immunization of rabbits with this protein led to arteriosclerotic changes of the aortic intima. In the last few years we have established this rabbit model for immunologic investigations of atherosclerosis and, in parallel, examined the pathogenesis of human atherosclerosis with regard to hsp 60/65 immune reactivity. Currently available data point to an autoimmune induction of early inflammatory arteriosclerotic changes triggered by a cellular and humoral immune reaction to stress-induced hsp 60-expressing areas of the endothelial cells.