It is now well recognised that antiphospholipid antibodies are associated with thrombosis and recurrent fetal loss. Some antiphospholipid antibodies (aPAs) have been shown to require a cofactor, beta 2 glycoprotein-I (beta 2 GPI), for binding to phospholipids, and recently beta 2 GPI has been identified as the antigenic target for some aPAs. beta 2 GPI possesses in vitro anticoagulant properties and modulation of beta 2 GPI function may therefore result in altered haemostatic regulation. In the present study, the influence of plasma derived aPAs and beta 2 GPI on factor XII activation on the surface of very low density lipoprotein (VLDL) was investigated. Factor XIIa generation was dependent on lipoprotein lipase treatment of VLDL and beta 2 GPI inhibited the factor XIIa generation in a concentration dependent manner. No consistent effects on factor XIIa generation were demonstrated with the IgG fractions from patients with aPAs. Inhibition of the beta 2 GPI activity was demonstrated by some antibodies, and study with cardiolipin affinity purified antibody indicated that antibody concentration is critical. These results suggest that perturbation of beta 2 GPI function may contribute to the pathogenic mechanism for thrombosis in some patients with aPAs.