Most autoantibodies associated with the antiphospholipid (aPL) syndrome and detected in standard anticardiolipin and/or lupus anticoagulant assays are directed against beta 2-glycoprotein I (beta 2-GPI) or prothrombin. Recent data indicate that these antibodies can also be detected in immunoassays utilizing purified protein antigens, in the absence of phospholipids. Initial clinical studies suggest that positivity in anti-beta 2-GPI immunoassays is more closely associated with the clinical manifestations of the aPL syndrome than is positivity in conventional anticardiolipin ELISAs. Anti-beta 2-GPI immunoassays may detect certain anti-beta 2-GPI antibodies that are not detectable in conventional anticardiolipin assays, but do not detect authentic (beta 2-GPI-independent) anticardiolipin antibodies. It appears that the former, but not the latter, antibodies are associated with the clinical manifestations of the aPL syndrome. The potential advantages and disadvantages of these new immunoassays in the clinical evaluation of the aPL syndrome are discussed.