Purpose <p>This study aimed to investigate the effects of concomitant proton pump inhibitor (PPI) use on the effectiveness of nivolumab in Japanese patients with advanced gastric cancer.</p> Methods <p>A single-center, retrospective, observational study was conducted at Keio University Hospital, Japan. We reviewed the medical records of consecutive patients with advanced gastric cancer treated with nivolumab monotherapy between September 2017 and March 2024 and compared treatment efficacy and safety with or without the concomitant use of PPIs. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Univariable and multivariable Cox proportional hazards models were used to estimate the hazard ratio (HRs) and 95% confidence intervals (CIs).</p> Results <p>Of the 84 patients included in this study, 46 were treated with PPIs. The median PFS was 2.1 (95% CI, 1.4–3.3) months in the PPI group and 4.4 (95% CI, 1.8–6.6) months in the non-PPI group (crude HR, 1.84; 95% CI, 1.15–2.95). The corresponding median OS was 5.3 (95% CI, 3.2–7.3) months and 7.3 (95% CI, 5.6–18.1) months (crude HR, 1.78; 95% CI, 1.10–2.89). Multivariable analysis revealed that PPI use significantly shortened both PFS and OS (adjusted HR, 1.79; 95% CI, 1.08–2.97 and adjusted HR, 1.72; 95% CI, 1.03–2.86, respectively).</p> Conclusion <p>Concomitant use of PPI may reduce the effectiveness of nivolumab in patients with advanced gastric cancer.</p>