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. We conducted a trial using the combination of cisplatin (100 mg/m2) and a 96-hour infusion of 5-FU (1000 mg/m2/day) and achieved a response rate of 88.5% in 26 patients treated with two courses. Five of these patients had complete remissions and 18 had partial remissions. Nausea and vomiting (experienced by 70% of the patients) was the predominant toxic effect, and 26% experienced leukopenia. Although all patients were initially inoperable, six underwent resection following chemotherapy, and another six underwent resection after chemotherapy and irradiation. Two additional patients were treated with radiation therapy after clinically achieving complete remissions following chemotherapy, and another ten 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.