S-1 is an oral 5-fluorouracil (5-FU) anticancer agent and has shown promising effects in the treatment of a wide range of carcinomas, including head and neck cancer. In addition to being used as adjuvant chemotherapy, S-1 is a promising agent for palliative treatment. Its ease of administration makes it an ideal drug to treat patients in the outpatient setting while maintaining adequate quality of life. However, the clinical role of S-1 in patients with recurrent/metastatic head and neck cancer is still uncertain. We retrospectively reviewed 16 patients with recurrent/metastatic head and neck cancer who received S-1 monotherapy. Thirteen patients with squamous cell carcinoma (SCC) and 3 patients with non-SCC who had recurrent/metastatic disease received S-1 monotherapy as outpatients. One patient with nasopharyngeal undifferentiated carcinoma and 1 patient with maxillary adenosquamous carcinoma showed complete response (CR), while all SCC patients showed stable disease (SD) or progressive disease (PD). Median time to progression (TTP) was 12 weeks. Five patients showed grade 3 and 4 adverse reactions, all hematological. Except for one episode of grade 4 leucopenia which required hospitalization and granulocyte colony-stimulating factor (GCSF) treatment, all adverse events resolved with dose reduction or dose omission. S-1 was safely administered in outpatients and showed some efficacy in the treatment of recurrent/metastatic head and neck cancer in patients who had received previous chemotherapy. S-1 could be used as palliative treatment in patients with recurrent/metastatic head and neck cancer.