Chemotherapy with cisplatin plus 5-FU infusion was given simultaneously with radiation therapy; both were administered every other week. Twenty-seven patients with stage IV disease and three with stage III disease were treated; 57% had T4, 33% had N3, and 10% had M1 disease. Of these patients, 17 (57%) achieved complete response and the rest achieved partial response. However, whether or not a clinically complete response occurred had no effect on subsequent risk for disease recurrence. With a median follow-up of 16 months (range, 6-35), only 11 patients (37%) have had disease recurrence and eight (27%) have died. Of those patients who recurred, six failed in distant sites only, one developed a second head and neck primary, and four (36% of all failures) failed regionally. Normally, greater than 50% of patients who are initially controlled (usually less than 60% of stage IV patients) would have failed within the first 12 months and greater than or equal to 75% of these would be expected to fail regionally. Nine patients who had received previous treatment or who had M1 disease accounted for six of the recurrences and four of the deaths. Because of the excellent local control, we have cautiously limited surgery to conserve laryngeal, tongue, and mandibular function in selected cases. Neither immediate nor long-term toxicity from radiation appeared increased. Although no patient with such advanced disease can be considered cured at this time, these results seem to represent a substantial improvement in the quality of life and degree of local control over other approaches. Controlled trials of the sequencing of radiation and chemotherapy in head and neck cancer appear indicated.