The Hoosier Oncology Group conducted a trial evaluating ifosfamide in patients who had recurrent or metastatic squamous cell carcinoma of the head and neck. Patients must have received no prior chemotherapy for metastatic disease. If prior adjuvant chemotherapy was given, the last cycle must have been at least six months from time of recurrence. All patients were required to have a Karnofsky performance status of > or = 50. Twenty-four patients received treatment consisting of ifosfamide, 1.5 g/m2/day for 5 days, with cycles repeated every 3 weeks. Mesna, 300 mg/m2, was administered intravenously 15 minutes before ifosfamide and 4 and 8 hours after ifosfamide on days 1 through 5. Toxicity was predominantly hematologic, with grade 3--4 neutropenia seen in 13 patients resulting in 4 episodes of neutropenic fever. One partial response was seen in 23 evaluable patients for an overall response rate of 4.3% (95% confidence interval, 0, 12.7%). In conclusion, ifosfamide would appear to have limited single-agent activity in squamous cell carcinoma of the head and neck.