The antiphospholipid syndrome (APS) is diagnosed by the occurrence of thrombosis and/or specific pregnancy morbidity. However, the diagnosis of APS is not easy and is hampered by several problems including high prevalence of clinical symptoms and high variability between different assays resulting in a high false-positive rate. Currently APS can be diagnosed for example by detecting anti-β2-glycoprotein I antibodies by ELISA. It has been reported that β2-glycoprotein I (β2GPI) changes its conformation from a native to an active form and thereby it opens up enabling antibodies to bind a specific epitope. We amongst others have shown that epitope glycine40-arginine43 of domain I of β2GPI is predominantly responsible for binding thrombosis related antibodies. Antibodies with affinity towards other epitopes have not been associated with thrombosis. Despite these results the question remains whether these domain I antibodies are the only antibodies of importance for the detection of APS.