The association of ifosfamide with cisplatin and 5-fluorouracil for the management of advanced squamous cell carcinoma of the head and neck was assessed in this trial. Ifosfamide was given initially to 12 patients in combination with standard fixed doses of cisplatin and 5-fluorouracil, at 1,000 mg/m2 daily on days 2, 3, and 4. Two patients died of neutropenia and severe infection, and the authors recruited seven more patients who were treated with a lower dose of ifosfamide, 800 mg/m2 daily on days 2, 3, and 4. One of the seven patients died of neutropenia and severe infection. Three complete remission were observed in 18 patients evaluable for efficacy. The study was closed early because of the severe toxicity profile demonstrated by this scheme and because of no clear advantage in efficacy versus cisplatin plus 5-fluorouracil combinations.