Background <p>Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has demonstrated survival benefits when combined with platinum-based chemotherapy in patients with CLDN18.2-positive gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, evidence regarding surgical intervention following zolbetuximab-based chemotherapy remains limited.</p> Case Presentation <p>We report four patients with CLDN18.2-positive, HER2-negative gastric or GEJ adenocarcinoma who underwent surgical intervention following zolbetuximab-based chemotherapy. Three patients initially had unresectable or marginally resectable disease and subsequently underwent conversion-intent or response-adapted surgical intervention after tumor regression and improvement of non-curative factors. One patient underwent pulmonary metastasectomy for metachronous oligometastatic disease after sustained systemic disease control. Zolbetuximab was administered in combination with mFOLFOX6 or CAPOX for a median of seven cycles. Macroscopic complete resection was achieved in three patients, whereas one patient had microscopic residual disease. No unexpected perioperative complications attributable to zolbetuximab were observed. These findings suggest that zolbetuximabbased chemotherapy may allow surgical intervention in carefully selected patients; however, the survival benefit of this approach remains unproven and requires further study.</p> Conclusions <p>Zolbetuximab-based chemotherapy may facilitate conversion-intent or response-adapted surgical intervention, including metastasectomy, in carefully selected patients with CLDN18.2-positive gastric and GEJ adenocarcinoma. A biomarker-driven, response-adapted multidisciplinary strategy may help identify candidates for surgery following CLDN18.2-targeted therapy, but larger studies are required to determine whether this approach improves survival outcomes.</p>