The prognosis of blast crisis (BC) of chronic myelogenous leukemia (CML) is extremely poor despite many efforts to induce remission with chemotherapy. We have recently treated a long-surviving CML patient who developed three separate episodes of BC. The administration of interferon-alpha (IFN-alpha) alone as maintenance therapy was incapable of preventing BC, which occurred twice in the first 2 years after the diagnosis of CML. Intensive chemotherapy using enocitabine, mitoxantrone, and etoposide was effective to induce hematological remission. Thereafter once per week oral administration of methotrexate (10-15 mg/week) was combined with IFN-alpha after the second BC. This treatment succeeded in obtaining a major cytogenetic response and keeping him in third chronic phase for 5 years until the last most recent third BC. We present here the rare clinical course of the patient, review the past literature, and discuss the efficacy of the combination of IFN-alpha and methotrexate in this disease.