Ten of 136 consecutive adult patients with previously untreated acute leukemia had morphologically undifferentiated leukemia by light microscopy. Leukemic cells from these patients were characterized by agranular cytoplasm, negative histochemical staining with sudan black (SB) and nonspecific esterase, and absent lymphoid cell surface markers and therefore were not classifiable according to the French-American- British (FAB) system. Electron microscopy with myeloperoxidase (MPO) staining revealed the presence of peroxidase positive cytoplasmic granules and endoplasmic reticulum in eight of the nine patients studied. Cells from the patient who was negative for MPO were also negative for platelet peroxidase. A series of monoclonal antibodies to myeloid antigens also revealed myeloid features with all patients having at least one myeloid differentiation antigen present on the surface of their cells. Common acute lymphoblastic leukemia (ALL) antigen was absent in the nine patients tested. Cytogenetic analysis of blast cells was abnormal in seven patients on whom adequately banded chromosomes were obtained although there were no consistent abnormalities. No patient had a Ph1 chromosome. Only two of the ten patients achieved a complete remission. Morphologically undifferentiated leukemia may have myeloid features when studied by transmission electron microscopy or with monoclonal antibodies for cell surface markers. Such studies should be performed when the leukemia cannot be classified using either light microscopy or lymphoid cell surface markers. Such patients infrequently achieve remission with standard therapy and constitute a distinct entity.