Thirty-seven patients with oral squamous cell carcinoma, many with advanced disease, were treated initially with a protocol using simultaneous intravenous 5-fluorouracil (5-FU) cis-platinum, and radiation. Twenty-two patients (62%) experienced complete remission after one cycle of therapy. Fifteen patients (38%) demonstrated an incomplete response; surgical resection was possible in 14 of these 15 patients. A second cycle of chemoradiotherapy was administered to all 37 patients. After this treatment resection is possible for some patients who are initially inoperable, and surgery is necessary only for those patients (38%) who show an incomplete remission after the first cycle of therapy and for those who present initially with bony invasion. Furthermore, the treatment of cervical nodes and intraoral disease may be divorced and the extent of surgery may be reduced for many patients. A 5-year survival of 76% is predicted for this group of patients. The described protocol shows promise for treatment of oral squamous cell carcinoma.