The long-term results of a multi-institutional study were analyzed in 101 cases (27 with stage III and 74 with stage IV) with advanced head and neck squamous cell carcinoma (HNSCC) given S-1 administration for 6 months after definitive treatments. The 3-year disease-free survival rate was 66.3% in cases overall. In terms of the survival rates in two groups with different administration methods, i.e., 2-week administration followed by 1-week rest or 4-week administration followed by 2-week rest, there was no significant difference. The risk factors of relapse were examined by multivariate analysis. The relapse rate increased according to the advancement of N staging and the higher risk of distant metastasis in cases with laryngeal (especially, supraglottic type) or hypopharyngeal carcinomas. Now, the efficacy of S-1 administration as adjuvant chemotherapy after definitive treatments for advanced HNSCC is under investigation,and the adequate administration period of S-1 should be evaluated in a controlled randomized study in future.