Background: S-1 plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. In patients with HER2-positive AGC, ToGA trial showed survival benefit with the addition of trastuzumab to capecitabine plus cisplatin or fluorouracil plus cisplatin and HERBIS-1 trial demonstrated promising antitumor activity with the addition of trastuzumab to SP. However, cisplatin has several important drawbacks, including nausea, vomiting, and renal toxicity. And these disadvantages of cisplatin are noticeable in elderly patients. We evaluated the efficacy and safety of trastuzumab combined with S-1 alone in elderly patients with HER-2 positive AGC. Methods: Patients, 65 years or older, with HER2-positive AGC received S-1 (80–120mg per day) orally on days 1–28 of a 42-day cycle and trastuzumab (course 1, 8 mg/kg; course 2 onward, 6 mg /kg) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary endpoints were overall survival (OS), progression free survival (PFS), time to treatment failure (TTF) and adverse events. The sample size was 40 to 60 patients estimated on the basis of threshold RR=20%, expected RR=35%, alpha=0.1 (one-sided) and power=80 to 90%. Results: A total of 51 patients were enrolled. One patient was ineligible, therefore in the full analysis set of 50 patients (actual statistical power = 87.5%), the median age was 71 years (range=65-85), male: female was 37:13 and ECOG PS was 0/1/2= 33/14/3. The confirmed RR (CR/PR/SD/PD=3/17/23/7) was 40.0% (80% confidence interval (CI); 31.1-48.9%, 95% CI; 26.4-53.6%), and the null hypothesis was rejected. The disease control rate was 86.0% (95% CI; 76.4-95.6%). Median OS, PFS, and TTF were immature. Major grade 3 or 4 adverse events included neutropenia (10.0%), anemia (24.0%), diarrhea (10.0%) and anorexia (12.0%). There was one treatment-related death. Conclusions: The primary end point was met. Trastuzumab in combination with S-1 alone demonstrated promising antitumor activity and manageable toxic effects in elderly patients with HER2-positive AGC. Clinical trial information: UMIN000007368.