Essential thrombocythemia (ET) and chronic myelogenous leukemia (CML) usually present with distinctive features. Citing experience with cases that overlap, the Polycythemia Vera Study Group recommends that negative tests for the Philadelphia chromosome be obtained before diagnosing ET. We describe two young women presenting with features absolutely typical for ET, including extreme thrombocytosis, no leukocytosis, no basophilia, no peripheral immature cells, and no splenomegaly. Severe thrombotic complications ensued: multiple cerebrovascular thromboemboli, pulmonary emboli, and miscarriage in one and myocardial infarction in the other. By 4 years, both developed leukocytosis, extreme basophilia, and circulating blasts, typical of accelerated CML. Cytogenetic studies were then performed, revealing the Philadelphia chromosome. Imatinib produced rapid clearing of blasts and basophils, but one woman later succumbed after allogeneic bone marrow transplant and the other has not achieved a major cytogenetic response. We conclude that CML can present in identical fashion as ET. The mandate for routine Philadelphia chromosome testing is magnified by the availability of targeted therapy and its greater efficacy in early stage disease.