Recent improvements in survival of patients with Ewing's sarcoma have been made since the addition of cyclophosphamide-based adjuvant chemotherapy to primary surgery and radiation. A potential limitation to cyclophosphamide use is its urotoxicity, primarily in the form of hemorrhagic cystitis. The incidence of this adverse effect in patients treated for Ewing's sarcoma has not been established. In a Mayo Clinic series of 116 patients with Ewing's sarcoma treated with cyclophosphamide, 17 (15%) developed hemorrhagic cystitis diagnosed on the basis of gross hematuria or cystoscopic findings (or both). Microscopic hematuria also occurred in 53% of patients (56 of 105 examined). The dose and duration of therapy appeared to be unrelated to the development of urotoxicity. Most patients recovered uneventfully with or without discontinuation of cyclophosphamide therapy, but a significant loss of blood occurred in three patients, and one patient required a cystectomy because of bladder fibrosis. Long-term follow-up is mandatory in these patients because of late recurrences of hemorrhagic cystitis or the possibility of bladder carcinoma. New therapies, directed at protecting the bladder from urotoxicity during cyclophosphamide treatment, are available.