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Summary. Background: Diagnosis of the antiphospholipid syndrome (APS) is difficult as a result of limited specificity of existing assays for detecting clinically relevant antiphospholipid antibodies. Anti-beta2-glycoprotein I (beta2GPI) antibodies play a central role in the disease process of APS. Objectives: We have investigated the relation between antiphospholipid antibodies with specificity for domain I of beta2GPI and thrombosis/pregnancy morbidity in an international multicenter study. Patients/methods: Four hundred and seventy-seven patients derived from nine different centres met the inclusion criterion of having anti-beta2GPI antibodies in their plasma/serum. Clinical data and results of tests for lupus anticoagulant, anti-cardiolipin antibodies and anti-beta2GPI antibodies were established at the different centres of inclusion. After being re-tested for the presence of IgG and/or IgM anti-beta2GPI antibodies, the samples were tested for the presence of IgG-directed against domain I of beta2GPI and results were correlated with the thrombotic and obstetric history. Results: Re-testing for the presence of anti-beta2GPI antibodies resulted in inclusion of 442/477 patients. IgG class anti-domain I antibodies were present in plasma of 243/442 patients (55%). 201/243 (83%) had a history of thrombosis. This resulted in an odds ratio of 3.5 (2.3–5.4, 95% confidence interval) for thrombosis. Anti-domain I IgG antibodies were also significantly correlated with obstetric complications [odds ratio: 2.4 (1.4–4.3, 95% confidence interval)]. Conclusion: In this multicenter study, the detection of IgG antibodies that are directed against domain I of beta2GPI proved to be more strongly associated with thrombosis and obstetric complications than those detected using the standard anti-beta2GPI antibody assay.