Abstract Background This study aimed to evaluate incidence risk and adverse clinical outcomes in COVID-19 disease among short-term users of acid-suppressants in South Korea. Methods This retrospective cohort study, conducted using a nationwide claims database for South Korea, used data from patients with COVID-19 tested between January 1 and May 15, 2020. Patients aged over 18 years and prescribed proton pump inhibitors (PPI) or histamine-2 receptor antagonist (H 2 RA) for more than 7 days were identified. Primary outcome was COVID-19 while secondary outcomes were all-cause mortality, hospitalization with respiratory disease, or intensive respiratory intervention. Large-scale propensity scores were used to match patients, while the Cox proportional hazard model was utilized to evaluate any association between exposure and outcome(s). The risk estimates were calibrated by using 123 negative control outcomes. Results We identified 26,166 PPI users and 62,117 H 2 RA users. After propensity score matching, compared to H 2 RA use, PPI use was not significantly associated with lower risk of COVID-19 (calibrated hazard ratio [HR], 0.81 [95% confidence interval (CI), 0.30–2.19]); moreover, PPI use was not associated with adverse clinical outcomes in COVID-19, namely, hospitalization with respiratory disease (calibrated HR, 0.88 [95% CI, 0.72–1.08]), intensive respiratory interventions (calibrated HR, 0.92 [95% CI, 0.46–1.82]), except for all-cause mortality (calibrated HR, 0.54 [95% CI, 0.31–0.95]). Conclusions In this study, we found that the PPI user was not associated with risk of COVID-19 compared to H 2 RA users. There was no significant relationship between severe clinical outcomes of COVID-19 and exposure to PPI compared with H 2 RA, except for all-cause mortality.