Anti-beta 2-GPI antibodies (a beta 2-GPI) were found in serum from patients with anti-phospholipid syndrome (APS) and/or systemic lupus erythematosus (SLE). Since a beta 2-GPI are often found in patients with anti-cardiolipin antibodies (aCL), their role in thrombosis as well as other central nervous system (CNS) manifestations in APS is unclear. We, therefore, investigated whether affinity-purified a beta 2-GPI bind the CNS. Astrocyte and neuron cell lines and histological sections were used as CNS substrates. Indirect immunofluorescence and/or streptavidin-biotin-peroxidase techniques revealed that astrocytes, neurons and vascular endothelium were bound by purified a beta 2-GPI (mouse monoclonal, rabbit polyclonal, human serum Ig a beta 2-GPI). This suggests a potential role for a beta 2-GPI in the CNS damage, as a beta 2-GPI might contribute to CNS pathology by either a direct interaction with astrocytes and neurons or an interaction with cerebral vascular endothelial cells. CNS immunoreaction was also demonstrated using six a beta 2-GPI-positive sera from patients (four with neurological manifestations). No binding to CNS was seen using a beta 2-GPI-negative sera, i.e. five from SLE patients (two with CNS involvement) and six healthy donors, or a monoclonal aCL without a beta 2-GPI immunoreactivity. Thus, the CNS reactivity by the a beta 2-GPI-positive sera appears specifically due to a beta 2-GPI and independent from aCL. Because of the presence of aCL in all patient sera, and the CNS involvement in three control patients, it is not possible to attribute a direct role for a beta 2-GPI in neurological diseases in this study.