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type:TOHO University Scholarly Publication, Original Article, Introduction: The effect of proton pump inhibitors on capecitabine- and S-1-based treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer is unknown. Therefore, we compared the effect of proton pump inhibitors between capecitabine- and S-1-based treatments for HER2-positive gastric cancer. Methods: In a multi-institutional study, we retrospectively analyzed the effect of proton pump inhibitors on 155 HER2-positive advanced or recurrent gastric cancer patients who were treated with oral 5-fluorouracil (capecitabine or S-1) and trastuzumab. Capecitabine- and S-1-based treatments were compared in terms of the response rate and time to treatment failure, and the negative effects of proton pump inhibitors on the treatment response were evaluated. In this study, the primary endpoint was the response rate, and the secondary endpoint was time to treatment failure. Results: There was no significant difference in the response rate between the capecitabine- and S-1-based treatments. However, in cases without proton pump inhibitor intake, the response rate significantly improved with capecitabine-based treatment rather than with S-1-based treatment (P = 0.046). Compared with the S-1-based treatment, the capecitabine-based treatment significantly prolonged the time to treatment failure (P = 0.044), including for patients with differentiated adenocarcinoma (P = 0.035). Conclusions: For HER2-positive and differentiated gastric cancer, capecitabine-based treatment may be better than S-1-based treatment. Proton pump inhibitors might decrease capecitabine's effects and should be avoided to increase the response rate to capecitabine-based treatment.