Based on encouraging results with 5-fluorouracil (5-FU), hydroxyurea, and concomitant radiotherapy in patients with advanced or recurrent head and neck cancer, an attempt was made to modulate the regimen by the addition of cisplatin as a third active agent. A cohort of 26 patients with head and neck cancer of all histologies were entered into a broad phase I study investigating simultaneous radiation therapy, 5-FU (with or without leucovorin), HU, and infusional cisplatin administered on an alternate-week schedule. Eleven patients (group 1) had failed prior curative local therapy and 15 patients (group 2) were considered to have a poor prognosis with standard therapy. The median follow-up was 30 months. The response rate for all evaluable patients was 82% (14/17), and the complete response rate was 65% (11/17). Patients in group 1 demonstrated a high failure rate (9/11), while few group 2 patients failed after treatment (2/15). The median time to progression was 4.4 months in group 1 and has not been reached in group 2. Patients in group 1 failed locally (7/11), while no local failures were observed in group 2. Acute and cumulative hematologic toxicity was encountered at all dose levels and schedules tested and prevented escalation of the cisplatin dose beyond the desired level of 100 mg/m2 per months. Mucositis was a second significant toxicity in patients with head and neck cancer and was more pronounced during cycles containing leucovorin. A detailed analysis of survival, time to progression, and site of failure is presented.