Proton pump inhibitors (PPIs) have been linked to an increased risk of Clostridium difficile infection (CDI) in observational studies. However, real-world evidence on the CDI risk of potassium-competitive acid blockers (P-CABs), a newer class of acid suppressants, is limited. Therefore, we conducted a retrospective cohort study using electronic health record data from 15 South Korean hospitals standardized to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) to assess CDI risk with P-CABs versus other acid-suppressive agents. Patients newly prescribed P-CABs, PPIs, or Histamine 2 Receptor Antagonists (H2RAs) between 2019 and 2024 were included, and the primary outcome was CDI occurrence. After 1:4 propensity score matching, pairwise comparisons were performed using Cox proportional hazards models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled across databases via meta-analysis. In the matched cohorts, pooled HRs were 0.87 (95% CI, 0.69–1.10) for P-CABs vs PPIs, 0.85 (0.64–1.12) for P-CABs vs H2RAs, and 1.13 (0.98–1.29) for PPIs vs H2RAs. Sensitivity analyses suggested a reduced CDI risk with P-CABs compared to PPIs under specific conditions, including in patients treated for ≥7 days (HR 0.75; 95% CI, 0.57–0.97), ≥14 days (0.73; 0.55–0.97), and in the as-treated approach (0.59; 0.31–0.91). In conclusion, in this multicenter study, P-CABs were not associated with increased CDI risk compared to PPIs or H2RAs.