Although its cell of origin is still controversial, the blastic NK-cell leukemia/lymphoma clearly represents a distinct type of hematopoietic neoplasm that is particularly clinically aggressive when it occurs in elderly patients as a disseminated, multi-organ disease. Consistently effective treatments have not been developed for this malignancy. The present report describes two elderly patients with widespread blastic NK-cell leukemia/lymphoma involving the skin, bone marrow, peripheral blood, lymph nodes, and viscera. In both cases the malignant cells were CD56+, CD2+, and terminal deoxynucleotidyl transferase (TdT) positive with no detectable T-cell receptor (TCR) gamma chain gene rearrangement. The cells also exhibited a low CD45 expression and strong CD99 (mic-2) expression, as seen in immature lymphoid malignancies. The above findings support the precursor NK-cell, rather than mature NK- or non-NK-cell, origin of the malignant cells. It is noteworthy that the two patients achieved complete responses to treatment with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate/cytarabine, a regimen currently utilized in acute lymphoblastic leukemia and high-grade lymphoma. The complete remission (CR) was sustained for 24 months in one patient who received four cycles (eight courses) of the treatment. It lasted 9 months in the second patient, who received only two cycles (four courses). If similar results are obtained with future patients, a randomized study comparing the hyper-CVAD regimen to other therapeutic strategies may be warranted. Copyright 2003 Wiley-Liss, Inc.