BACKGROUND Previous small studies have demonstrated positive immunohistochemical staining in rabbit and human atherosclerotic plaques by antibodies that recognize oxidized low-density lipoprotein (OxLDL), but none have examined a large number of human coronary arteries or evaluated whether epitopes recognized by these antibodies might be present on plaque proteins other than OxLDL. RESULTS Immunohistochemistry was performed on atherosclerotic (n = 87) and nonatherosclerotic (n = 51) coronary arterial segments from 20 patients by use of monoclonal antibodies that recognize epitopes on macrophages, smooth muscle cells, apolipoprotein (apo) B, and OxLDL. Staining with the OxLDL antibody (Ox5) was much more prevalent in atherosclerotic than in control segments. Extracellular Ox5 staining colocalized with apo B, but cell-associated Ox5 staining occurred in the absence of cell-associated apo B staining, which suggests that cell-associated epitopes for Ox5 were on proteins other than LDL. Epitopes for Ox5 formed in vitro on two readily available non-apo B proteins, human serum albumin and apo A-I, when these proteins were incubated under conditions of oxidant stress with polyunsaturated but not monounsaturated fatty acids; furthermore, an antioxidant inhibited Ox5 epitope formation. Thus, epitopes for Ox5 can form on proteins other than apo B. Also, phorbol ester-treated macrophages cultured in apo B-free medium developed epitopes for Ox5. CONCLUSIONS These findings are consistent with the hypothesis that atherosclerosis is associated with oxidative modification of proteins in addition to LDL, particularly cell-associated proteins, and that the antiatherosclerotic effects of antioxidants seen in some studies may not be solely due to prevention of LDL oxidation.