In patients with clinical symptoms of coronary atherosclerosis, T cells are activated and directed to autologous proteins contained in the active plaques, suggesting that autoimmune responses may play a role in atherosclerosis progression. Organ-specific autoimmune diseases are sometimes accompanied by broad alterations of serum autoreactive antibody repertoires. We thus investigated antibody repertoires at a global level, using a technique of immunoblotting that allows for the quantitative screening of antibody reactivities in complex antibody mixtures toward a large panel of antigens derived from homologous tissue extracts, followed by multiparametric statistical analysis of the data. We analyzed the autoreactive IgG repertoire in 20 patients with documented coronary atherosclerosis and in 20 matched healthy controls. Total proteins from atherosclerotic carotid specimens and normal arterial tissues (target organs) and from kidney, liver, and stomach (non-target control organs) were used as panels of antigens. Patients had a significantly perturbed antibody repertoire and an enhanced autoreactivity of IgG to target and non-target organs, as compared with controls. Reactivity of purified IgG to plaque and normal artery proteins was greater in patients, but reactivity of IgG in the whole serum toward normal arterial tissue was lower than in controls; this suggests that, in patients, autoreactivity toward normal arteries is regulated by serum factors. Our data indicate that atherosclerotic patients develop a perturbed humoral immune response directed toward arterial proteins, which impacts on the overall autoreactive repertoire. These findings further substantiate that autoimmune processes take place in atherosclerosis and most likely influence disease progression.