BACKGROUND: Gastric cancer is a common malignant tumor, and radical gastrectomy can markedly improve the prognosis of gastric cancer patients. However, some patients are diagnosed with advanced gastric cancer before receiving any antitumor therapy and need to receive neoadjuvant chemotherapy (NACT). Previous studies have shown that NACT may cause gut barrier dysfunction and intestinal dysbacteriosis which may further lead to infections. Probiotics have the potential to reduce postoperative infections and improve short-term outcomes after abdominal surgery; however, no large-sample, multicenter, randomized clinical trials have been conducted to explore the effectiveness of probiotics in gastric cancer patients receiving NACT. So we proposed a hypothesis that probiotics can improve short-term outcomes after minimally invasive radical gastrectomy in gastric cancer patients receiving NACT and designed this multicenter randomized controlled trial with the objective to verify this hypothesis. METHODS/DESIGN: The GISSG 2023-01 study will be a prospective, open-label, multicenter RCT to verify whether perioperatively probiotic supplementation (begin from the end of the last cycle of NACT to postoperative day 7 or the discharge day) can reduce postoperative infections and improve recovery of gastrointestinal function and other short-term outcomes after minimally invasive radical gastrectomy in gastric cancer patients receiving NACT. A total of 318 patients who meet the inclusion criteria will be enrolled in this study and randomly divided into two groups in a 1:1 ratio: the probiotic group (n = 159) and the control group (n = 159). The participants in the probiotic group will receive perioperative probiotic supplementation, and those in the control group will receive blank control management. The other perioperative management protocols will be the same between the two groups. The primary outcome is postoperative infection compared between the two groups, and the secondary outcomes are postoperative recovery of gastrointestinal function, quality of life, laboratory parameters of systemic inflammation and other short-term outcomes. DISCUSSION: The results of this RCT should clarify whether perioperative probiotic supplementation would reduce postoperative infection, promote recovery of gastrointestinal function, reduce laboratory parameters of systemic inflammation and improve symptoms and quality of life after minimally invasive radical gastrectomy in gastric cancer patients receiving NACT. It is hoped that our data will provide evidence that probiotic supplementation improves short-term outcomes in gastric cancer patients receiving NACT. TRIAL REGISTRATION: This trial has been registered on https://clinicaltrials.gov/(NCT05901779 ).