Acute promyelocytic leukemia (APL) has been historically characterized by a high rate of early hemorrhagic death, particularly from intracranial bleeding. The hemorrhagic complications have been attributed to a combination of intravascular thrombin generation, excessive fibrinolysis and/or proteolytic activities released from blast cells. Before the era of all-trans retinoic acid (ATRA), the incidence of early fatal bleeding in recent series has ranged from 8 to 46%, and no anti-hemorrhagic treatment clearly appeared superior in abating this complication. This uncertainty is due to remain because of the lack of prospective studies. The increasing awareness of the need for prompt diagnosis and treatment of APL and the larger availability of supportive therapy has largely contributed to lessen the incidence of fatal bleeding, which can be reliably estimated around 10% in major centers. Groups pioneering the use of ATRA have reported a rapid improvement of the coagulopathy of APL, usually starting 48 h from the beginning of the treatment. However, the hemostatic changes during ATRA have been monitored only in a few patients and recent results suggest that hyperfibrinolysis/proteolysis is rapidly corrected by ATRA, whereas thrombin generation may persist longer. Moreover, although significantly less frequent, fatal bleeding may occur during ATRA and thrombotic events have also been reported so that hemostatic death rate is also approximately 10% in patients treated with ATRA. The combination of chemotherapy plus ATRA administration during induction has been suggested as a useful means of controlling hyperleukocytosis, and this could contribute in abating this unacceptably high rate of early death. On the other side, chemotherapy can dramatically exacerbate clotting abnormalities leading to catastrophic clinical outcomes. Thus, more detailed studies of the coagulopathy of APL and its changes during treatment with ATRA, or ATRA combined with chemotherapy, are required in order to offer the most appropriate treatment to these patients still at risk of severe bleeding and thrombotic complications.