Abstract Background: A potential association between proton-pump inhibitors (PPI) and gastric cancer remains undefined. Thus, we aimed to evaluate such association within the Stomach cancer Pooling (StoP) Project. Methods: Data from five case–control studies of the StoP Project were included (1,889 cases and 6,517 controls). We assessed the impact of different exposure definitions, specifically any reported use of PPIs and exposure definitions based on the duration of PPI intake. Additionally, we modeled the dose–response relationship between the cumulative duration of PPI intake and gastric cancer. Results: Significant associations between PPI intake and gastric cancer, both overall and in the stratified analyses, were limited to exposure definitions based on short durations of intake. The overall odds ratio (OR) for any reported PPI intake was 1.78 [95% confidence interval (CI): 0.76–4.14]. In the dose–response analysis, the ORs of gastric cancer were found to be higher for short durations of PPI intake (6 months: OR 3.26; 95% CI: 2.40–4.42; one year: OR 2.14; 95% CI: 1.69–2.70; 2 years: OR 1.50; 95% CI: 1.22–1.85; 3 years: OR 1.27; 95% CI: 1.03–1.56), with the association becoming not significant for durations longer than 3 years. Conclusions: Our findings suggest that the observed association between PPIs and gastric cancer might be mainly due to reverse causality. Impact: The results of this study suggest that PPIs are a safe therapeutic choice regarding their effect on the occurrence of gastric cancer. See related commentary by Richman and Leiman, p. 1127