Anti-ß2glycoprotein I (anti-ß2GPI) antibodies constitute the main autoantibody specificity in the sera of patients with antiphospholipid syndrome (APS). There is evidence that anti- ß2GPI antibodies induce the precoagulant activity of the endothelium by cross-linking the ß2 glycoprotein I (ß2GPI) on the cell surface. Since ß2GPI lacks intracellular domains, homology with other molecules such as CD40 that could initiate signaling, was extensively searched. A 86% homology between the amino acid position 239-245 of the CD40 and 7-13 of the ß2glycoprotein was found. The CD40 peptide corresponding to amino acids 239-245 of the CD40 molecule was synthesized and coupled to a multiple antigenic peptide carrier. Antibodies to CD40 peptide were found in 61.5% APS patients (n=39), in 72.7% of systemic lupus erythematosus (SLE) positive for anti-ß2GPI antibodies (n=11) and 31.6% of SLE negative for anti- ß2GPI antibodies (n=19), but not in rheumatoid arthritis patients (n=28) or controls (n=36). Antibodies to CD40 peptide were associated with arterial thrombosis and/or brain microinfarcts. Affinity purified anti-CD40 peptide antibodies as well as affinity purified anti-ß2GPI antibodies recognized both, the ß2GPI and the CD40 peptide. The specificity of this recognition was confirmed with homologous and heterologous inhibition experiments. Confocal microscopy experiments demonstrated this cross-recognition of CD40 and ß2GPI molecules, by the purified anti-CD40 peptide antibodies, at the protein level. Thus, antibodies reacting with the ß2GPI can react and potentially activate different cells which express CD40 molecules at their surface.