Unless they undergo transplantation, all patients with chronic myeloid leukemia (CML) will eventually develop a late phase of acute blast crisis (ABC). Although additional chromosomal abnormalities to the Philadelphia (Ph) chromosome may herald ABC in many CML cases, the mechanisms leading to this fatal event are obscure. Viral etiology, including the Epstein-Barr virus (EBV) has never been implicated in the pathogenesis of ABC in CML. Iloprost is an analogue of epoprostenol (prostacyclin; PGI2) commonly used for the treatment of peripheral vascular diseases and acts via inhibition of platelet activation, and by vasodilation. A case of ABC with blasts of undetermined lineage showing EBV infection in a male patient with Ph positive CML is described here. This unusual event developed during a course of treatment with the prostacyclin analogue, iloprost administered for vasculopathic leg ulcers. The proliferating blasts stained positively by immunohistochemistry only for the leukocyte common antigen (LCA/CD-45), and the EBV-latent membrane protein 1 (LMP-1). The only chromosomal abnormality detected by cytogenetic analysis was the conventional Ph-chromosome. It is suggested that ABC in this case of CML, was associated with EBV-activated blasts of undetermined lineage.