Despite the discovery of anti-endothelial cell antibodies (AECA) in a heterogeneous group of disorders characterized by endothelial damage, their pathogenic role is still debated. Experimental in vitro models indicate that they can either damage endothelial cells or trigger cell signaling by reacting with as yet undefined surface molecules. However, clinical studies suggest that, in addition to AECA, other pathogenic mechanisms are involved in the vasculitic process. Recently, antibodies specific for b2 glycoprotein I, the phospholipid-binding protein targeted by anti-phospholipid antibodies, have been shown to display anti-endothelial activity. These autoantibodies recognize b2 glycoprotein I adhered to the endothelium and induce a cell perturbation that might underlie the thrombophilic state of the antiphospholipid syndrome.