Background: The efficacy of trastuzumab has been established for HER2-positive advanced gastric cancer patients with metastatic disease. However, it remains unclear if the addition of trastuzumab to preoperative chemotherapy is effective for treatment of HER2-positive locally advanced gastric cancer. Methods: Eligible patients with HER2-positive gastric cancer with extensive lymph node metastasis were randomized to preoperative S-1/cisplatin (SP) (group A) or SP plus trastuzumab (group B). In both groups, patients received S-1, 80–120 mg/body, on days 1–14 and cisplatin, 60 mg/m², on day 1, q21, 3-4 courses. Additionally, in group B, patients received infusions of trastuzumab (first course 8 mg/kg followed by 6 mg/kg, day 1). After gastrectomy, adjuvant chemotherapy with S-1 was performed for 1 year in both groups. The primary endpoint was overall survival, and the sample size was planned to be 130 patients in total, expecting a 10% increase in the 3-year overall survival (70% vs 80%) with a 1-sided alpha of 0.2, a power of 0.75. Results: The study was terminated in March 2021 due to slow patient accrual. In total, 46 patients were randomized to either group A (22 patients) or group B (24 patients). Patient characteristics were well balanced between the groups. Planned preoperative chemotherapy was completed in 20 patients (90.9%) in group A and in 23 patients (95.8%) in group B, and R0 resection was achieved in 20 patients (90.9%) in group A and 22 patients (91.7%) in group B. The incidences of grade 3 or 4 hematological/non-hematological adverse events during preoperative chemotherapy were 27.3/18.2% in group A and 4.2/8.3% in group B. Objective response rate (CR/PR) tended to be higher in group B (66.7% [16/24]) than in group A (36.4% [8/22], p = 0.08). Pathological response rate (> grade 1b in Japanese classification, 22.7% [5/22] vs. 50.0% [12/24], p = 0.07) and the proportion of patients achieving downstage to ypStage 0/I/II (22.7% [5/22] vs. 50.0% [12/24], p = 0.07) were also higher in group B than in group A. Conclusions: Preoperative chemotherapy with SP plus trastuzumab was feasible, and tended to show better radiological and pathological response rates. Better survival outcomes are expected by adding trastuzumab to preoperative chemotherapy with SP for locally advanced gastric cancer with extensive nodal metastasis. Clinical trial information: UMIN000016920.