Initial treatment with drug combinations that include cisplatin and bleomycin has been effective in reducing tumor in patients with previously untreated epidermoid cancers of the head and neck. Because of the threat of pulmonary complications from bleomycin, patients with poor pulmonary function were excluded from those studies. A trial was conducted using the combination of cisplatin (100 mg/m2) and a 96-h infusion of 5-FU [5-fluorouracil] (1000 mg/m2 per day) and achieved a response rate of 88.5% in 26 patients treated with 2 courses. Five of these patients had complete remissions; 18 had partial remissions. Nausea and vomiting (experienced by 70% of the patients) was the predominant toxic effect; 26% experienced leukopenia. Although all patients were initially inoperable, 6 underwent resection following chemotherapy; another 6 underwent resection after chemotherapy and irradiation. Two additional patients were treated with radiation therapy after clinically achieving complete remissions following chemotherapy; another 10 received X-ray therapy after chemotherapy. Cisplatin and 5-FU infusion are effective without being as toxic as bleomycin in patients with previously untreated advanced carcinoma of the head and neck.