Antiphospholipid syndrome (APS) is a systemic autoimmune disease, associated not only with a hypercoagulable state and recurrent fetal loss but with many diverse clinical manifestations including heart involvement, neurological manifestations, as well as skin, kidney and hematologic abnormalities. Cardiac manifestations include coronary by-pass graft and angioplasty occlusions, cardiomyopathy, cyanotic congenital heart disease, intracardiac thrombus and complications of cardiovascular surgery. The valvular heart disease was defined as Libman–Sacks nonbacterial endocarditis. Previously, we have shown a linear subendothelial deposition of anti-cardiolipin/β 2 glycoprotein I (β2GPI) antibodies in the valve specimens derived from APS patients. The involvement of complement C3c in the pathogenesis was documented. We assessed the β2GPI-related target epitope recognized by the anti-β2GPI Abs on the valves.In order to find the β2GPI-related target epitopes recognized by the anti-β2GPI antibodies on the valves, we used β2GPI-related synthetic peptides. The presence of anti-β2GPI Abs on the studied valves was detected by anti-idiotypic antibody, followed by immunoperoxidase analysis. Biotin attached to the N-terminal of β2GPI-related synthetic peptides and control peptide were used to identify the epitope addressed by the anti-β2GPI Abs deposited on the patient's valve. The binding was probed by streptavidin-peroxidase and appropriate substrate. The specificity was confirmed by competition assays with control peptide and anti-idiotypic antibody.Among the β2GPI-related synthetic peptides, two peptides were found in previous studies to mimic common pathogens either bacteriae or viruses, which raised a possible infectious origin for APS. One of these peptides, TLRVYK, is a specific target for anti-β2GPI Abs deposited on the APS valves. This synthetic peptide was able to displace the anti-anti-β2GPI anti-idiotypic Abs for binding the anti-β2GPI Abs on the valve by a competition assay.We point to the possibility that Libman–Sacks nonbacterial endocarditis may have an infectious origin.