The acute transformation of chronic myeloid leukemia has become a rare event since the introduction of tyrosine kinase inhibitors. Less than 3% of patients with CML transform to a megakaryoblastic leukemia. The diagnosis represents a challenge, due to the frequent association with myelofibrosis, thus requiring an osteo-medullar biopsy to confirm the diagnosis. We report the case of a megacaryoblastic blast crisis associated with myelofibrosis in a CML young female patient. A 32-year-old woman previously diagnosed with CML in chronic phase, on Tyrosine kinase inhibitors, presents with a clinical bone marrow failure. Blood counts showed pancytopenia. A peripheral blood smear revealed the presence of 30% blast cells, with a round nuclei, prominent nucleoli, and a very basophilic cytoplasm with cytoplasmic blebs. The diagnosis of a blast crisis in CML was retained. Bone marrow aspiration was practiced twice, and came back poor both times. A bone marrow biopsy practiced later confirming the diagnosis of acute leukemia associated to myelofibrosis. Immunophenotyping by flow cytometry was performed on peripheral bood, and revealed a blast population (76%) positive for CD45 (mild) and expressing the following markers CD33, CD34, CD41 and CD61, confirming the diagnosis of acute megacaryoblastic leukemia. Based on clinical presentation, bone marrow findings and flow cytometry, the diagnosis of CML with megakaryoblastic crisis associated to myelofibrosis at a 32-year-old woman was retained.