The recommended S-1 chemotherapy schedule for head and neck cancer is daily treatment for 4 weeks, followed by 2 weeks of rest. However, this can lead to adverse events and sometimes treatment withdrawal. Alternate-day treatment with a pyrimidine anticancer agent is reported to reduce adverse events without compromising anticancer activity. We examined the indication of alternate-day treatment with S-1 for oral cancer. Fifteen patients(3 men and 12 women; average age: 81.3 years)with oral squamous cell carcinoma started consecutive-day treatment with S-1. Treatment had to be interrupted after 0.5-10 courses because of grade >2 myelosuppression, hepatorenal and electrolyte disorder, and grade 1 digestive toxicity. After a recovery period of 8-168 days from adverse events, alternate-day treatment with S-1 was started. Adverse events on this regimen were grade 2 leucopenia and hyperbilirubinemia in some patients. It was possible for 10 of the patients to continue this treatment for longer than 1 year or until death, but 5 patients could not continue because of a recurrence of a renal or electrolyte disorder, pneumonia, or disease progression. It is thought that alternate-day treatment with S-1 reduces the incidence of adverse events compared to consecutive-day treatment, and can allow continuous administration. Alternateday treatment with S-1 for female patients aged over 80 years with grade 1 leucopenia and/or thrombocytopenia before administration may help to maintain their quality of life.