The results of the Japan Clinical Oncology Group trial demonstrated that adjuvant chemotherapy with S-1 for stage II/III gastric cancer is effective and suggested that this therapy should be adopted as the standard treatment following curative D2 gastric dissection. We reviewed treatment outcomes in 58 consecutive patients who received adjuvant therapy with S-1 for stage II/III gastric cancer following curative D2 dissection; the standard dosage used was determined on the basis of the patient body surface area. Twenty-four patients (41.3%) discontinued treatment before 12 months. Patients who completed 12 months of adjuvant therapy with S-1 were younger and more frequently treated by senior doctors (>15 years of experience) than those who did not. However, no differences existed in pathological features and surgical procedures between groups. Overall survival and relapse-free survival were better in patients who completed 12 months of adjuvant therapy with S-1. Fatigue and nausea were associated with discontinuation of S-1 treatment. In conclusion, immediately after surgery, fatigue and gastrointestinal symptoms of ≤ grade 2 may have a major impact on treatment compliance. Prior to the commencement of S-1 administration, both patients and doctors should be made completely aware of the toxicity, compliance and efficacy issues associated with this adjuvant therapy.