The patient is 11-year-old girl who was diagnosed as having hybrid acute leukemia (myeloid and lymphoid) from morphological (cytochemistry) findings, immunophenotype and genotype. During reinduction therapy after a second relapse, she presented hepatosplenomegaly and the remittent fever unresponsive to the intensified antibiotics. The diagnosis of reactive histiocytosis was made because of the remarkable elevation of serum ferritin value and proliferation of mature histiocytes in the bone marrow. Treatment with etoposide resulted in the disappearance of her fever and other symptoms. The subsequent refractoriness to platelet transfusion was also overcome by etoposide (p.o.) therapy. The results suggested that the treatment with etoposide might be effective for reactive histiocytosis and the related refractory state to platelet transfusion during therapy for leukemia.