We introduced concurrent neoadjuvant chemoradiotherapy (CCRT) with S-1, an oral fluoropyrimidine, as treatment for oral squamous cell carcinoma (OSCC) from October 2005. The clinical usefulness and medical safety of CCRT with S-1 (S-1 group) for OSCC were analyzed and compared with CCRT using super-selective intra-arterial infusion (AI group). The subjects in the S-1 group underwent external irradiation, at a total dose of 30 Gy, with S-1 chemotherapy. The AI group received cisplatin (CDDP) or carboplatin (CBDCA) combined with daily radiotherapy at a total dose of 40 Gy. The histological effects and disease-specific survival rates were almost equivalent in the S-1 and AI groups. Adverse events were less frequent in the S-1 group, while hematological toxicity, including anemia, thrombopenia and pharyngeal edema, was observed in the AI group. The results of this study indicate that CCRT combined with S-1 is a more effective and safer treatment for OSCC than AI.