This study investigated the prevalence of antibody against annexin II (A2) in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). It also explored the role of this antibody in thrombosis. Purified recombinant A2 was used in ELISA to measure the levels of IgG anti-A2 antibody in 101 APS patients, 41 SLE patients with thrombosis, 124 SLE patients without thrombosis, and 120 healthy controls. The positive rates of IgG anti-A2 antibody in APS patients and SLE patients with thrombosis were 21.8 and 26.8%, respectively. Both values are significantly higher than that in SLE patients without thrombosis (6.5%). IgG anti-A2 antibody is associated with thrombosis and/or pregnancy morbidity (P < 0.001). The data show that the levels of anti-A2 antibody are higher in APS patients and SLE patients with thrombosis. Further, the presence of this antibody is associated with thrombosis and/or pregnancy morbidity, suggesting that anti-A2 antibody may be helpful in identifying potential APS cases.