There is accumulating evidence showing that lupus anticoagulants (LA) are more strongly associated with thrombosis than anticardiolipin antibodies. In addition, indirect evidence has been presented indicating that beta2GPI-dependent LA are more strongly associated with thrombosis than prothrombin-dependent LA. From this, one may assume that anti-beta2GPI antibodies with LA activity are more pathogenic than anti-beta2GPI antibodies without LA activity. Therefore, it is of the utmost importance to understand the molecular basis on which some anti-beta2GPI antibodies behave as LA. In this presentation, the current knowledge on the interaction of beta2GPI with phospholipids and with anti-beta2GPI antibodies is reviewed and an integrated model for the anti-beta2GPI-dependent LA activity is proposed with implications for a pathogenic role of these particular antibodies.