Abstract The benefit of the effect of chemotherapy in patients with advanced head and neck squamous cell tumors have been demonstrated by recent meta-analyses of randomized studies. However, the role of chemotherapy—especially in advanced oral cancer—is not fully clear, because of the very small amount of phase II literature available. From January 1994 to December 2000, a total of 44 pts aged 33–75 years (mean age 60 years) with advanced and histologically proved squamous cell carcinoma's of the oral cavity received at least one chemotherapy course. Seven patients had stage III and 37 stage IV disease. The chemotherapy was the initial therapy in a group of 21 patients. In a second group of 23 patients the chemotherapy was delivered after relapse of their disease. The pre-chemotherapy treatment of the second group was radiotherapy in 11, surgery in 4, combination of radiotherapy and surgery in 8 patients. The chemotherapy regimen consisted of cisplatin 100 mg/m 2 in 3-h infusion, day 1 and 5-FU 1000 mg/m 2 in 24-h infusion, days 1–5. Treatment was repeated every 21 days. A total of 154 treatment courses (3.5 per patient, ranged 1–10) were administered. Myelotoxicity, nausea and vomiting were the major treatment complications. The overall response rate to the induction chemotherapy was 52.3%, with 19% complete (CR), and 33.3% partial response's (PR) and to the chemotherapy for recurrent/metastatic disease 30.4% with 8.7% CR, and 21.7% PR. No difference was found in the median survival of the two subgroups (12 months). The median survival of the responders was 15 months (95% CI 11.3–18.7 months), and of the non-responders 9 months (95% CI 5.6–12.4 months) ( P=0.0067). Chemotherapy with cisplatin and 5-FU combination is effective in pts with advanced squamous cell oral cancer and appears to improve the survival of patients who have a good response.