In this study, we evaluated the clinical performance of anti-beta 2-glycoprotein 1 domain 1 antibodies (a beta 2GP1-D1) in the diagnosis of antiphospholipid syndrome (APS). Sera from 229 subjects were tested, including 35 patients with primary APS, 51 patients with APS associated to other diseases, 30 patients with non-APS thrombosis, 32 patients with non-APS pregnancy-related morbidity, 42 patients with systemic lupus erythematosus, and 39 healthy controls (HC). Serum IgG a beta 2GP1-D1, IgG/IgM anti-cardiolipin (aCL) and IgG/IgM a beta 2GP1 were measured by a chemiluminescence assay. The levels of IgG a beta 2GP1-D1 were significantly increased in patients with APS, compared with disease controls and HCs (p < 0.001). Significant correlation was identified between IgG a beta 2GP1-D1 and IgG a beta 2GP1 (p < 0.0001), indicating IgG a beta 2GP1-D1 were the predominant domain-specific antibodies in IgG a beta 2GP1 family. Importantly, a beta 2GP1-D1, but not a beta 2GP1 non-D1, was significantly correlated with thrombotic events. Interestingly, no significant correlation between IgG a beta 2GP1-D1 and obstetric complications was observed. Additionally, significantly higher levels of IgG a beta 2GP1-D1 were found in patients with triple aPL positivity, compared with patients with double and single aPL positivity. Our findings suggest a potential role of IgG a beta 2GP1-D1 in identifying APS patients with high risk of thrombosis, shedding insight on the introduction of IgG a beta 2GP1-D1 in China.