The disease spectrum of natural killer (NK) cell leukemias and lymphomas has recently been expanding with the continuing evolution in diagnostic concepts. We describe here seven cases of acute leukemia of conceivable myeloid and NK cell precursor phenotype in six men and one woman varying from 19 to 59 years of age (median, 46 years). Striking extramedullary involvement was evident at initial presentation, with peripheral lymphadenopathy and/or mediastinal masses. Two lacked any leukemic cells in the bone marrow at diagnosis. Using cytochemical myeloperoxidase staining, less than 3% of the leukemic cells showed positive reactivity. However, expression of CD7, CD33, CD34, CD56, and frequently HLA-DR, but not other NK, T-cell, and B-cell markers was observed. Cytoplasmic CD3 was detected in three of the cases by flow cytometry and in six by Northern blotting, suggesting an origin from common progenitors between the NK cell and myeloid lineages. All but one presented germline configurations of the T-cell receptor beta and gamma chain genes and Ig heavy chain gene. With regard to morphology, the cells were generally L2-shaped, with variation in cell size, round to moderately irregular nuclei and prominent nucleoli, pale cytoplasm, and a lack of azurophilic granules. Histopathologic examination of biopsied specimens of extramedullary tumors showed a lymphoblast-like morphology, implying the differential diagnostic problem from lymphoblastic lymphomas, especially in cases lacking bone marrow involvement. Three patients were successfully treated with chemotherapy for acute myeloid leukemia (AML), whereas three other patients proved refractory to chemotherapeutic regimens for lymphoid malignancies, although two responded to subsequent AML chemotherapy. However, despite intensive chemotherapy, including allogeneic bone marrow transplantation, most persued fatal courses within 41 months. These data suggested that the CD7+ and CD56+ myeloid/NK cell precursor acute leukemia might constitute a distinct biologic and clinical disease entity. Its recognition appears to be particularly important for the clinicopathologic evaluation of CD56+ hematolymphoid malignancies and the development of therapeutic approaches to such disease.