Lymphohistiocytic erythrophagocytosis (LE) is a usually fatal disease characterized by fever, organomegaly, hyperlipidemia, central nervous system involvement, and cellular immunodeficiency. Treatment with corticosteroids, cytotoxic chemotherapy, and blood exchange is unsuccessful. We have treated two children with the epipodophyllotoxin VP-16 and with intrathecal chemotherapy. Each patient had an initial complete response, and one remains in remission 36 months after therapy began. Aziridinylbenzoquinone (AZQ) therapy induced a complete response in a patient who relapsed during VP-16 therapy. A combination of VP-16 and intrathecal chemotherapy appears to be the most effective therapy for LE, and further evaluation of the role of AZQ is indicated.