Background. Evidence regarding the use of proton-pump inhibitors (PPIs) in COVID-19 patients remains elusive. Aim. To examine the potential effects of PPI use on the clinical outcomes of COVID-19 patients in a territory-wide cohort. Methods. A retrospective cohort study was performed using data from a territory-wide database in Hong Kong. Patients diagnosed with COVID-19 from 23 January 2020 to 1 January 2021 were identified by virological results. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. PPI users were identified by PPI use within 12 months prior to their diagnosis of COVID-19. Results. We identified 8,675 COVID-19 patients (mean age 46 years, 49% male, 97.6% of all reported cases in Hong Kong), of which 579 (6.7%) patients had used PPI. PPI users were found to be older, more likely to have comorbidities, concomitant medications and unfavourable laboratory parameters than nonusers. Of the 8,675 COVID-19 patients, 500 (5.8%) developed the primary endpoint. After propensity score (PS) balancing for patients’ demographics, comorbidities, laboratory parameters, and use of medications, PPI use was not found to be associated with the development of primary endpoint in PS weighting (weighted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.82–1.46, P = 0.529 ), and PS matching analysis (weighted HR 0.79, 95% CI 0.56–1.13, P = 0.198 ). Consistent nonassociation was observed after multivariable adjustment (adjusted HR 0.84, 95% CI 0.67–1.06, P = 0.142 ), and in subgroups of current and past PPI users. Conclusion. PPI use is not found to be associated with adverse clinical outcomes in COVID-19 patients. The result remains robust after PS weighting, PS matching, and multivariable adjustment.