Background <p>To improve the prognosis of clinically resectable type 4 or large type 3 gastric cancer (GC), we performed a phase I/II study of neoadjuvant-radiotherapy combined with S-1 plus cisplatin.</p> Patients and Methods <p>Phase I, with a standard 3 + 3 dose-escalation design, was performed to define the recommended phase II dose. Efficacy and safety were evaluated in phase II. The three dose levels were as follows: level 0, S-1 60&#xa0;mg/m² on days 1–14 plus cisplatin 60&#xa0;mg/m² on day 1; level 1, S-1 80&#xa0;mg/m² on days 1–14 plus cisplatin 60&#xa0;mg/m² on day 1; and level 2, S-1 80&#xa0;mg/m² on days 1–14 and 22–35, plus cisplatin 60&#xa0;mg/m² on days 1 and 22. The starting dose was level 1. Radiotherapy was delivered at a total dose of 40 Gy in fractions for 4 weeks.</p> Results <p>A total of six patients were enrolled in the phase I study. Dose-limiting toxicity was observed at level 2; level 1 was established as the recommended phase II dose. In phase II, 20 patients were enrolled from November 2012 to April 2018. Grade 3/4 leukopenia and nonhematologic adverse events occurred in 35% and 5% of the patients, respectively. In total, 19 patients underwent the protocol surgery; 2 (10.5%) achieved a pathological complete response. There were no treatment-related deaths; 3- and 5-year overall survival rates were 70.0 and 50.0%, respectively.</p> Conclusions <p>Neoadjuvant chemoradiotherapy with S-1 plus cisplatin is a safe and promising treatment for clinically resectable type 4 or large type 3 GC.</p>