Objective The presence of autoantibodies against a cryptic epitope in domain I of beta 2-glycoprotein I (beta 2GPI) is strongly associated with thrombotic events in patients with the antiphospholipid syndrome. We hypothesized that a conformational change could be a trigger for the formation of antibodies against domain I of beta 2GPI. Therefore, we investigated whether immune responses against beta 2GPI are related to its conformation. Methods. Conformational changes in beta(2)GPI were studied using various techniques, either upon binding to cardiolipin or after disruption of the internal disulfide bonds. The immunogenicity of beta(2)GPI in different conformations as well as the individual domains of beta(2)GPI were studied in vivo by monitoring the generation of antibodies after intravenous administration of beta(2)GPI to mice. Furthermore, plasma samples from these mice were assessed for lupus anticoagulant activity and thrombin-antithrombin complex levels. Results. We observed that the interaction of beta(2)GPI with cardiolipin induced a conformational change in beta(2)GPI: electron microscopy revealed that beta(2)GPI assembled into polymeric meshworks. We next investigated the immunogenicity of both human and murine beta(2)GPI in mice. Both human and murine beta(2)GPI combined with cardiolipin and misfolded beta(2)GPI triggered antibody formation against the native protein as well as against domain I of beta(2)GPI, while native beta(2)GPI was not immunogenic. In addition, we observed that anti-domain I antibodies developed in mice injected with domain I of beta(2)GPI, and that antibodies did not develop in mice injected with domains II-V. The induced anti-domain I antibodies prolonged the dilute Russell's viper venom plasma clotting time. The plasma of mice with anti-domain I antibodies had increased levels of circulating thrombin-antithrombin complexes. Conclusion. The results of our studies indicate that the exposure of cryptic epitopes due to conformational changes in beta(2)GPI can induce autoantibody formation.