A 68-year-old female was hospitalized because of general fatigue and edema. Physical examination revealed anemia and splenomegaly, and laboratory tests showed severe hypoproteinemia and pancytopenia. She was splenectomized and diagnosed as histiocytic sarcoma showing diffuse infiltration of large histiocytic cells (LCA-, CD45RO-, CD20-, CD15-, CD30-, CD35-, CD68+ FDC+, fascin+). While any test including gastrointestinal endoscopy and bone marrow cytology did not detect infiltration of the sarcoma cells, hypoproteinemia and pancytopenia continued after splenectomy. An alpha anti-trypsin test revealed protein-losing gastroenteropathy. Despite of CHOP therapy-resistance, treatment with etoposide and prednisolone improved hypoproteinemia and pancytopenia.