BACKGROUND Non-organ-specific autoantibodies are present in centenarians without evidence of autoimmune diseases but conflicting or no data on anti-phospholipid and anti-phospholipid binding proteins were reported. OBJECTIVE To investigate the presence and antigen specificity of anti-phospholipid and anti-phospholipid binding proteins in centenarians. METHODS Seventy-seven centenarians, 70 adult controls, 65 unselected elderly subjects, and 38 old SENIEUR volunteers were investigated. Anti-cardiolipin, anti-human beta 2 glycoprotein I, and lupus anticoagulant were detected. Antigen specificity was assayed against plates coated with anionic, neutral and cationic phospholipids and beta 2 glycoprotein I-dependence was also evaluated. RESULTS 54.3% of the centenarians were positive for IgG and 8.6% for IgM anti-beta 2 glycoprotein I antibodies, while only 20.7% centenarians were positive for anti-cardiolipin IgG and 2.59% for IgM; none resulted positive for lupus anticoagulant. Anti-cardiolipin positive sera cross-reacted with negatively charged phospholipids and displayed decreased binding to serum-free cardiolipin-coated plates that was restored by human beta 2 glycoprotein I or fetal calf serum. CONCLUSIONS Centenarians display high reactivity against human beta 2 glycoprotein I but low binding to the bovine molecule in the anti-cardiolipin assay. In spite of the presence of antibodies comparable to those found in patients with the anti-phospholipid syndrome, no vascular events were reported suggesting the presence of unknown protective factors and/or the lack of triggering factors.