Background: RESOLVE study shows clinically meaningful improvement in perioperative SOX in patients with locally advanced GC/GEJC undergoing D2 gastrectomy. Addition of PD-1 inhibitor to chemotherapy shows significant clinical benefit in first-line treatment of advanced GC/GEJC. This trial was designed to compare the perioperative sintilimab combined with SOX versus perioperative SOX in patients with resectable locally advanced GC/GEJC. Methods: PERSIST is a multicenter, prospective, open-label, randomized-controlled phase II study. Patients with histologically or cytologically confirmed GC/GEJC, clinical stage II-III, no previous systemic treatment, ECOG performance status (PS) of 0 or 1 were eligible for inclusion. Patients will be randomized (1:1) to received either perioperative sintilimab (200 mg d1 Q3W, three cycles preoperatively and up to 1 year postoperatively) in combined with SOX (oxaliplatin 130 mg/m² d1, oral S-1 40–60 mg BID d1-14 Q3W, three cycles preoperatively and five cycles postoperatively) in experimental group or perioperative SOX alone in control group. The primary endpoint was the pCR rate. The secondary endpoints were the MPR rate, down-staging rate, 3-years DFS rate, 5-years OS rate, safety. The study is registered with Clinicaltrials.gov: NCT04982939. Results: As of September 2022, 101 patients were enrolled, with median age 61 years (range 31-75 years), males 85 (84.2%), cT2/3/4/X 2(2.0%)/5(5.0%)/93(92.1%)/1(1.0%), cN0/1/2/3/X 10(10.0%)/42(41.6%)/27(26.7%)/9(8.9%)/13(12.9%), and GC/GEJC 92(91.1%)/9(8.9%). Forty-seven patients (experimental group:26, control group:21) underwent radical resection and all achieved R0 resection. The pCR rates in the experimental group and control group were 26.9% (95%CI 11.6%-47.8%) and 4.8% (95%CI 0.1%-23.8%), respectively. The MPR rates in the experimental group and control group were 69.2% (95%CI 48.2%-85.7%) and 28.6% (95%CI 11.3%-52.2%), respectively. 76.9% (20/26) and 52.4% (11/21) patients achieved down-staging in the experimental group and control group. Three patients developed grade 3–4 surgical complications. Grade 3–4 TRAEs included thrombocytopenia (4.0%), anemia (3.0%), neutropenia (2.0%), allergic reaction (2.0%), pneumonia (1.0%), myocardial infarction (1.0%). The median postoperative hospital stay in the experimental and control group were 10 days (range 7-38 days) and 11 days (range 7-66 days). Conclusions: Compared to SOX chemotherapy alone, sintilimab combined with SOX resulted in an encouraging pCR rate, MPR rate and downstaging rate as perioperative treatment for resectable locally advanced GC/GEJC, and safety was manageable. Clinical trial information: NCT04982939.