A phase II study was performed to assess the safety and efficacy of ifosfamide and mitoxantrone in recurrent and/or metastatic squamous cell carcinomas of the head and neck. Treatment consisted of ifosfamide 1500 mg/m2 in 1000 ml saline, infused over 60 min and mesna 20% of the total dose of ifosfamide in three doses for 3 days combined with mitoxantrone 12 mg/m2 given as a short infusion on day 1. Treatment courses were repeated every 4 weeks until a total of six cycles. Twenty-two patients entered this trial, 13 of whom had received chemo- and radiation therapy, and nine patients who underwent radiation therapy with or without prior surgery. We observed no objective response, with the exception of two patients who experienced minor response (reduction of tumor size of 25%). The dose-limiting toxicity was myelosuppression with grade 3/4 leukocytopenia in seven patients (32%) and grade 3/4 neutropenia in 15 (68%). Severe organ toxicity except alopecia (91%) was not observed. Ifosfamide combined with mitoxantrone does not improve the therapeutic armentarium in recurrent squamous cell carcinoma of the head and neck.