Chemotherapy has not significantly altered the overall survival of patients with recurrent squamous cell carcinoma of the head and neck; therefore, the development of new agents is essential. The purpose of the current phase II study was to define the efficacy of ifosfamide in the treatment of recurrent squamous cell carcinoma of the head and neck. All patients were required to have squamous cell carcinoma of the head and neck that had recurred following surgery or radiotherapy or both. Patients may have received prior chemotherapy. Patients were initially treated with ifosfamide 2 g/m2/day for 4 days (dose level 0). Dose level-1 was 2 g/m2/day for 3 days, and dose level-2 was 2 g/m2/day for 2 days. All patients received mesna 400 mg/m2/day prior to and 1,200 mg/m2/day as a continuous infusion after ifosfamide. Thirty-eight patients were enrolled in the study. Five patients were inevaluable for toxicity or response. Overall, the regimen was well tolerated, with grade 4 granulocytopenia the only significant toxicity occurring in 16 patients. Overall, eight of 31 evaluable patients (25.8%) had a major response. Only one of the 10 patients (10%) with prior chemotherapy responded, but seven of the 21 patients (33.3%) with no prior chemotherapy had major responses. Ifosfamide is an active agent in recurrent squamous cell carcinoma of the head and neck. Further studies of ifosfamide in combination with other agents, particularly as induction therapy in patients with locally advanced disease, are warranted.