C-reactive protein (CRP) is one of the strongest independent predictor of cardiovascular disease (CVD). We have previously reported that oxidized LDL (oxLDL) interacts with ss2-glycoprotein I (ss2GPI), implicating oxLDL/ss2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/ss2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/ss2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, non-complexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining co-localized CRP and ss2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of atherosclerosis. Serum levels of CRP correlated with soluble forms of ICAM-1 and VCAM-1, and oxLDL/ss2GPI complexes correlated with total cholesterol and hemoglobin A1c. Thus, the generation of CRP/oxLDL/ss2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/ss2GPI complexes can be distinguished from pyrogenic non-complexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.