We aim to clarify beneficial effect of pre-operative radiation with chemotherapy in highly advanced gastric cancer patients, evaluating histological response, toxicity and patients' quality of life (QOL). We used pre-operative radiation with S-1 and low-dose cisplatin to treat 8 patients with highly advanced gastric cancer (clinical stage IV) in a pilot study. Clinical staging after therapy showed 5 PRs (partial response), 2 NCs (no change), and 1 PD (partial disease) following evaluation of the primary tumor and suspicious metastatic lesions in the lymph nodes, esophagus, liver, and peritoneum, for a response rate of 62.5% (5/8 cases). Of 8 patients, 6 underwent surgery, and 2 of these 6 patients had a histologically complete response (grade 3 effect) and 3 patients had a partial response (grade 2 effect), suggesting that a high histological response (5/6 cases; 83.3%) is expected by the chemoradiation. The survival analysis showed that 5 out of the 8 patients died within 10 months after initiating therapy, while 3 patients are alive without recurrence at 15, 18, and 30 months after therapy, suggesting a relatively good outcome for clinical stage IV gastric cancer. All cases showed grade 2-4 bone marrow suppression toxicity and/or grade 0-2 gastro-intestinal toxicity, while 5 out of 8 patients (62.5%) showed improvement in appetite loss at the end of the therapy, indicating that the patients' quality of life (QOL) was preserved. Chemoradiation may be a powerful regimen for obtaining histological response with tolerable toxicity and improved QOL in highly advanced gastric cancer patients.