The antiphospholipid antibody syndrome is an autoimmune condition in which venous or arterial thrombosis and recurrent pregnancy losses occur in patients having serologic evidence of antibodies against anionic phospholipid-protein complexes. The pathophysiologic mechanisms of this syndrome have not yet been established. Annexin-V, an anionic phospholipid-binding protein with potent anticoagulant activity, is necessary for maintenance of placental integrity and may play a thromboregulatory role at the vascular-blood interface by forming two-dimensional crystals which shield anionic phospholipids from complexing with coagulation proteins from circulating blood. We propose that thrombosis and pregnancy loss in the antiphospholipid syndrome may be caused by disruption of this Annexin-V shield by antiphospholipid (and cofactor) antibodies, thereby increasing the net quantity of thrombogenic phospholipids exposed to the circulating blood. The data accumulated from tissue immunohistochemistry, trophoblast and endothelial cell culture studies, coagulation studies using noncellular phospholipids, and competition studies on artificial phospholipid bilayer are consistent with the hypothesis that interference with the binding of Annexin-V to anionic phospholipid surfaces is an important mechanism of thrombosis and pregnancy loss in the antiphospholipid syndrome.