Because prior chemotherapy in patients with disseminated reticulum cell sarcoma had been unsatisfactory, cyclophosphamide (Cytoxan) therapy was evaluated. The 66 patients had documented disease so widespread that radiotherapy to symptomatic areas was no longer feasible; 42% had remissions with greater than 50% objective improvement for 2 to 22 months. If possible, an initial dose of 25 to 40 mg/kg was administered intravenously in divided daily doses over 4 to 5 days. Because second courses of therapy were ineffective, oral maintenance therapy was employed after initial response. Careful titration of dosage with particular attention to pretreatment therapy minimized toxicity. Only one death from hepatic insufficiency and one from gram-negative sepsis and leukopenia were drug-related. Patients less than 13 years old, with central nervous system involvement, or in the leukemic phase did not respond. Over-all survival has not altered significantly in the past 20 years, with a 10 month, 50% survival from diagnosis. Nevertheless, cyclophosphamide, because of its effectiveness, minimal toxicity and ease of dosage control, is the treatment of choice at present for effective palliation of patients with disseminated reticulum cell sarcoma when radiotherapy is no longer possible.