The possibility of a genetic predisposition to develop the antiphospholipid syndrome (APS) and to produce anticardiolipin antibodies and lupus anticoagulant has been addressed by family studies and by population studies. Various studies suggest a familial occurrence of anticardiolipin antibodies and lupus anticoagulant, with or without clinical evidence of APS. This familial tendency could be genetically determined. Multiple human leukocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described. Genetic studies of beta(2)-glycoprotein-1(GP1) polymorphisms have been determined and valine/leucine polymorphism could be a genetic risk for having anti-beta(2)-GP1 antibodies and APS. Compared with polymorphism of beta(2)-GP1 as a genetic risk factor for APS, beta(2)-GP1 deficiency is not associated with thrombosis and patients with APS usually have normal or somewhat elevated levels of beta(2)-GP1. The antigen specificity of antiphospholipid antibodies and the pathophysiology of thrombosis in APS are highly heterogeneous and multifactorial.