Background <p>Perioperative chemotherapy is an important treatment option for resectable locally advanced gastric cancer (LAGC). However, completing planned cycles remains challenging for patients. This study aimed to investigate the effect of treatment completion on the survival of patients with poor tumor regression following perioperative chemotherapy.</p> Methods <p>This multicenter retrospective study reviewed the data of patients with LAGC who underwent perioperative chemotherapy and curative resection and had a tumor regression grade of 2 or 3 (i.e., at least 10% residual tumor cells in surgical specimens) at three teaching hospitals in China. To evaluate the impact of completing all cycles of perioperative chemotherapy on the 3-year overall survival (OS) and recurrence-free survival (RFS), patients who completed all treatment cycles were compared with those who did not, using overlap weighting.</p> Results <p>A total of 441 poor responders were included, of whom 239 (54.2%) completed all cycles of perioperative chemotherapy. After weighting, no significant differences were found in the 3-year OS (67.3% vs. 58.4%, P = 0.122) and RFS (58.4% vs. 51.9%, P = 0.293) between the complete and incomplete groups. However, completion of perioperative chemotherapy was significantly associated with improvements in 3-year OS (89.6% vs. 65.0%, P = 0.002) and RFS (79.5% vs. 56.7%, P = 0.004) in the ypN0 subgroup, but not in the ypN1–3 subgroup (3-year OS: 58.1% vs. 55.7%, P = 0.788; 3-year RFS: 49.7% vs. 49.8%, P = 0.892), with a significant interaction effect (P = 0.012 and 0.016, respectively). Several sensitivity analyses, including a landmark analysis, confirmed the robustness of these results.</p> Conclusion <p>The association between completion of perioperative chemotherapy and survival appeared to be heterogeneous across ypN subgroups among patients with LAGC with poor response in a postoperative decision context, highlighting the need for prospective validation.</p>