Acute leukemia occurred in two women after prolonged chemotherapy for metastatic carcinoma of the breast. Palliative radiation therapy was given to both patients within 18 and 22 months, respectively, before the onset of acute leukemia, but the short interval between radiation therapy and the onset of leukemia did not suggest radiation leukemogenesis. Therapy included prolonged administration of cyclophosphamide and chlorambucil and intermittent administration of prednisone, vincristine, 5-fluorouracil, and methotrexate. The second patient received 6 months of hexamethylmelamine therapy in addition.The types of leukemia and the time interval from chemotherapy are similar to reported cases of acute leukemia during alkylating agent therapy of multiple myeloma, chronic lymphocytic leukemia, and carcinoma of the ovary and lung.