The purpose of this study was to evaluate the maximum tolerated dose, dose-limiting toxicities and preliminary efficacy of chemotherapy with cisplatin, docetaxel and S-1 (TPS) to treat advanced head and neck squamous cell cancer. S-1 was administered orally twice daily on days 1-14 and docetaxel and cisplatin were injected intravenously on day 8, with one course lasting 4 weeks. The recommended dose obtained from a phase I study was set at docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 80 mg/m(2)/day. The phase II study revealed that the overall response rate was 81%, comprising 95% in untreated patients with localized advanced cancer and no distant metastases, 50% in untreated patients with distant metastases and 33% in previously treated patients with recurrence. The overall survival rate of untreated patients with localized advanced cancer and no distant metastases was 95% at 1 year and 64.33% at 2 years. In terms of grade 3 or higher hematotoxicity, neutropenia occurred in 100%, thrombocytotopenia in 4% and anemia in 4%. Febrile neutropenia occurred in 46%, with the rate rising to 57% in elderly patients ≥66 years. Grade 3 or higher non-hematotoxicity consisted of loss of appetite in 8%, diarrhea in 8%, hyponatremia in 13% and hypokalemia in 13%. This TPS therapy may be recommended for use as induction chemotherapy. For patients ≤65 years, the appropriate dose was docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 80 mg/m(2), whereas for those ≥66 years, it was docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 60 mg/m(2).