The prognosis of type 4 or large type 3-gastric cancer is extremely poor. Despite various perioperative adjuvant therapies; as JCOG0501, peritoneal recurrence is still difficult to control. Since the clinical efficacy of chemo-radiotherapy was suggested for the treatment of advanced gastric cancer, chemo-radiotherapy is a promising strategy for curatively resectable type 4 or large type 3-gastric cancer. This multicenter, phase II study evaluated the efficacy and safety of radiotherapy combined with S-1 plus cisplatin for this target. Eligibility criteria included pathologically confirmed gastric adenocarcinoma with macroscopically type 4 or large type 3, without peritoneal or distant metastases. Patients received preoperative chemo-radiotherapy with S-1 80 mg/m2/day from Day 1 to 14 and cisplatin 60 mg/m2 on Day 1, and radiotherapy at a total dose of 40 Gy in 20 fractions was delivered for 4 weeks, followed by D2 gastrectomy, and received S-1 monotherapy for one year postoperatively. The primary endpoint was the pathological complete response rate (% protocol completion). Secondary endpoints were safety, overall survival, and the response rate (RR). The sample size was calculated to be 30 cases, under the hypothesis of expected % pathological complete response rate of 15% and threshold pathological complete response rate of 2% with one-sided testing at the 10% significance level and power of 90%. From November 2012 to April 2018, 20 patients were enrolled. A median age of 20 patients was 67 years. Nineteen patients had protocol operation, and two of them showed pathological complete response (10.5%; 95% confidence interval 1.3–33.1%, p < 0.001). During preoperative chemotherapy, grade 3/4 neutropenia occurred in 25%, and grade 3/4 non-hematological adverse events occurred in 10%. The incidence of adverse events related to surgery was occurred in 31.6% patients. There were no treatment-related deaths. Follow-up for long-term survival is continuing. Notably the pathological RR (residual tumor < 2/3) was 100% (19/19). Preoperative chemo-radiotherapy with S-1 plus CDDP is a safe and promising treatment for type 4 or large type 3 gastric cancer. Osaka Gastointestinal Cancer Chemotherapy Study Group. Has not received any funding. All authors have declared no conflicts of interest.