Induction (proto) chemotherapy consisting of 3 courses of cisplatin and 120-hour 5-fluorouracil infusion was administered to 88 patients who had locally advanced, previously untreated head and neck cancer. The majority (81%) of these patients were classified as stage IV, and 17% had second primary carcinomas of the upper aerodigestive tract. An overall response rate of 94% was observed, with a 54% incidence of complete clinical response. The toxicity of the chemotherapy was judged acceptable, and no life-threatening or fatal drug-related side effects occurred. Twenty-four percent of the patients failed to comply with recommended standard treatment. In patients achieving a complete clinical response, 47% refused recommended surgery. Any response less than a complete clinical response to induction chemotherapy was not associated with any survival advantage. We conclude that future research efforts should be directed toward the identification of chemotherapeutic regimins that maximize the incidence of complete clinical response. In addition, any large-scale chemotherapy trial in patients with resectable disease should avoid the use of an induction sequence to minimize compliance problems with standard treatment.