Bleeding in acute promyelocytic leukemia (APL) is mainly associated with disseminated intravascular coagulation and hyperfibrinolysis. Annexin II (Ann II) is a co-receptor for plasminogen and tissue plasminogen activator (tPA). This study demonstrates that abnormally high levels of Ann II expression in APL cells increase the production of plasmin. Hyperfibrinolysis could be corrected by all-trans retinoic acid (ATRA) or ATRA plus arsenic trioxide therapy in patients with APL. SiRNA targetting Ann II caused a decrease in tPA-dependent plasmin generation, while Ann II cDNA transfectant stimulated plasmin production. These results suggest that Ann II play an important role in hyperfibrinolysis in APL.