A young adult woman with no significant past medical history presented with marked leukocytosis. The blood smear showed 50% blasts (panel A, single arrow [original magnification ×1000; Wright-Giemsa stain]) in a background of neutrophilia with myelocytes and promyelocytes, eosinophilia (panel A, double arrows), and basophilia (panel B, arrow [original magnification ×1000; Wright-Giemsa stain]). The morphologic findings raised the possibility of a blast phase of chronic myelogenous leukemia (CML). However, atypical large purple granules were noted in the eosinophils (panel A, inset [original magnification ×1000]), suggesting an acute myeloid leukemia (AML) with inv(16). Cytogenetic analysis (panel C) did reveal coexistence of t(9;22)(q24;q11.2) and inv(16)(p13.1q22) in all 20 cells analyzed, and fluorescence in situ hybridization was positive for BCR-ABL1 fusion in 44% of the cells (panel D [original magnification ×1000; DAPI [4′,6-diamidino-2-phenylindole] counterstain]) and CBFB rearrangements in 19.5% of the cells (panel E [original magnification ×1000; DAPI counterstain]). These 2 genetic abnormalities were also identified in the neutrophils (panel F [original magnification ×1000; DAPI counterstain]).De novo AML with coexistence of t(9;22) and inv(16) is rare, and limited data suggest that these cases have as favorable a prognosis as AML with inv(16) alone. However, coexistence of inv(16) in CML seems to have an unfavorable prognosis with rapid disease progression to accelerated or blast phase. The presence of BCR-ABL1 and CBFB rearrangements in the neutrophils in this case indicates that these abnormalities likely precede AML, most suggesting a blast phase of CML. The patient received chemotherapy and dasatinib, underwent a bone marrow transplant, and has been in molecular remission.