Abstract Background and Aims Proton pump inhibitors (PPI) are commonly used drugs worldwide and have been linked to worsening renal function and incident chronic kidney disease. Recently, potassium-competitive acid blockers (P-CAB) have emerged as alternative gastric acid-reducing agents with a comparable effect as PPIs. However, little is known about the renal safety of P-CAB. We aimed to compare the renal outcomes of patients treated with P-CAB and those treated with PPI. Method We retrospectively identified all patients who were prescribed P-CAB (tegoprazan) or PPI (esomeprazole) for 30 days or more in outpatient clinics of a tertiary care center between 2019 and 2023. Longitudinal serum creatinine data and various demographic and clinical variables were collected. Renal outcomes were defined as creatinine doubling or decline in estimated glomerular filtration rate (eGFR) of 30%. Patients with baseline eGFR < 15 mL/min/1.73 m2 and those who do not have sufficient creatinine measures to assess renal outcomes were excluded. Cox proportional hazard analyses were performed for renal outcomes with adjustment of multiple clinical covariates. Results Among 8 436 patients with a mean followup of 21 months, 2 214 and 6 222 patients were treated with P-CAB and PPI, respectively, for esophageal and gastric diseases. P-CAB group showed lower rates of creatinine doubling (Log-rank P = 0.001) and decline of eGFR (Log-rank P = 0.001) compared to PPI group. P-CAB use was associated with a 0.50-fold (95% confidence interval [CI] 0.33–0.75) lower risk for creatinine doubling and 0.58-fold (95% CI 0.42–0.81) lower risk for eGFR decline in unadjusted analysis. After adjusting multiple covariates including baseline eGFR, prescription days, major comorbidities, and concomitant use of other medications, hazard ratios for creatinine doubling and eGFR decline were 0.64 (95% CI 0.42–0.98) and 0.73 (95% CI 0.53–1.02), respectively. Conclusion Use of P-CAB is associated with a lower risk for renal function deterioration compared to PPI. Given the renal safety concerns of PPIs, using P-CAB could be a relatively safer strategy for preserving kidney function in patients who need long-term gastric acid suppression. Further studies with a larger cohort incorporating other P-CABs are required to validate this finding.