Background: Recently, immunotherapy combined with trastuzumab and chemotherapy have been recommended by the clinical guidelines of many countries as the first-line treatment for advanced HER2-positive G/GEJ adenocarcinoma. Combining chemotherapy with tislelizumab and trastuzumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable HER2-positive GC/GEJC. Methods: This study is a multicenter, single-arm, open-label phase 2 study (NCT04819971). Patients with histologically confirmed cT2-4NxM0 or cTxN+M0, (TNM 8th edition), resectable gastric adenocarcinoma are eligible for this study. Neoadjuvant therapy will be administered for four cycles. The patients will receive tislelizumab and trastuzumab for 1 cycle (Q3W), followed by tislelizumab and trastuzumab combined with DOS (Docetaxel + Oxaliplatin + S-1) for 3 cycles (Q3W). Surgery is planned 4-6 weeks after preoperative treatment. Patients who have complete surgical resection will receive adjuvant therapy starting within 4–6 weeks after surgery for 6 cycles (three cycles of tislelizumab and trastuzumab combined with DOS regimen, followed by 6 weeks of tislelizumab and trastuzumab for 6 cycles. The primary endpoint was pathological complete response rate (pCR). Secondary endpoints included R0 resection rate, 1-year and 2-year event-free survival (EFS), overall survival (OS) and safety. Results: From September 13, 2021 to February 01, 2023, 12 patients were enrolled (58.0% male, median age 61 years old), and the median follow up time was 7.3 months (0.4-16.9). Seven patients completed surgery, and 5 patients were undergoing neoadjuvant therapy. The R0 resection rate was 100%, 3 patients (42.9%) achieved pCR, and 4 patients (57.1%) achieved major pathological remission (MPR). Postoperative pathology showed tumor downstaging in 5 cases after neoadjuvant therapy, with a decrease rate of 71.4%. Median OS and EFS have not been reached. The most common AEs (all grades, grade ≥3) were anemia in 1 (8.3%) and neutropenia in 1 case (8.3%). The immune-related adverse events were all grade 1 included 2 thyroid dysfunction (16.7%), 1 abnormal liver function (8.3%), and 1 of elevated blood sugar (8.3%). No grade 3 or higher immune-related AE was observed. No treatment related deaths were reported. Conclusions: According to the preliminary results, tislelizumab combined with trastuzumab and standard chemotherapy in the perioperative period of HER2-positive GC and EGJ have a good clinical benefit trend and controllable security. Clinical trial information: NCT04819971.