Patients with systemic histiocytosis (Letterer-Siwe Disease, Hand-Schüller-Christian Disease, and Eosinophilic Granuloma) were treated at our Center using combined modality therapy involving surgery, radiation therapy, and single or combination agent chemotherapy. The records of 148 patients were reviewed; 127 patients were evaluable with histopathologically confirmed diagnosis of disease classifiable to one of the above categories. Based on follow-up information with median follow-up time 8.5 years from diagnosis, a staging system was developed to classify patients according to severity of disease and prognosis. Children whose disease was diagnosed before they were 24 months of age, had a significantly worse prognosis than older children independent of number of systems involved, or number of bone lesions. Twenty-one patients were irradiated to the hypothalamus for attempted control of diabetes insipidus (D.I.); in 4 patients, complete reversal of symptoms and signs of DI occurred; they were able to discontinue pitressin for 2, 5, 5 and 25 years. Eighty-nine patients received radiation therapy in the course of their management to 380 fields for attempted control of bone lesions. In patients whose bone lesions were treated to doses ranging between 100 and 2000 rad, local control was achieved in 95% of courses. The absence of a dose-response curve in the radiocurability of local bone lesions reflects severity of other systems involvement, propensity for spontaneous resolution of lesions, and concomitant chemotherapy. Based on our analysis, radiation therapy is recommended, particularly for painful lesions and for large lesions of weight bearing bones and the axial skeleton. These data support the use of local radiation therapy in systemic histiocytosis for attempted control of diabetes insipidus, and in specific instances for control of painful or potentially debilating bone lesions.