Abstract: Medicine ® Observational Study OPEN Effect of aspirin on coronavirus disease 2019 A nationwide case-control study in South Korea Minkook Son, MDa, Myung-giun Noh, MDa, Jeong Hoon Lee, PhDb, Jeongkuk Seo, MDc, ∗ Hansoo Park, MD, PhDa, Sung Yang, PhDa,d, Abstract Several studies reported that aspirin can potentially help prevent infection and serious complications of coronavirus disease (COVID19), but no study has elucidated a definitive association between aspirin and COVID-19. This study aims to investigate the association between aspirin and COVID-19. This case-control study used demographic, clinical, and health screening laboratory test data collected from the National Health Insurance Service database. Patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until June 4, 2020, were matched with control patients using propensity score matching according to their SARS-CoV-2 status, the composite of complications, and death. The composite of complications included intensive care unit admission, use of vasopressors, high-flow oxygen therapy, renal replacement therapy, extracorporeal membrane oxygenation, and death. Exposure to aspirin was defined as having a prescription for aspirin for more than 14 days, including the index date. After matching, multivariableadjusted conditional logistic regression analysis was performed. To confirm the robustness of this study, we used 2 study groups, 3 propensity score matching methods, and 3 models for conditional logistic regression analyses. The crude odds ratio and 95% confidence interval for SARS-CoV-2 infection between the groups without and with exposure to aspirin were 1.21 (1.04–1.41), but the adjusted odds ratios (95% confidence interval) were not significant. There was no association between aspirin exposure and COVID-19 status. Multiple statistical analyses, including subgroup analysis, revealed consistent results. Furthermore, the results of analysis for complications and death were not significant. Aspirin exposure was not associated with COVID-19-related complications and mortality in COVID-19 patients. In this nationwide population-based case-control study, aspirin use was not associated with SARS-CoV-2 infection or related complications. With several ongoing randomized controlled trials of aspirin in COVID-19 patients, more studies would be able to confirm the effectiveness of aspirin in COVID-19. Abbreviations: CCI = Charlson Comorbidity Index, CI = confidence interval, COVID-19 = coronavirus disease, KCDC = Korea Centers for Disease Control and Prevention, NHIS = National Health Insurance Service, NSAIDs = nonsteroidal anti-inflammatory drugs, OR = odds ratio, PSM = propensity score matching, SMD = standardized mean difference, WHO = World Health Organization. Keywords: aspirin, COVID-19, infections, Republic of Korea Editor: Bruno M. Carneiro. MS and MN contributed equally to this work. This work was supported by the National Research Foundation of Korea (NRF) grant, funded by the Korea government (MSIT) (No. 2020R1A5A8018367 and 2021R1A2C3008169). The funders had no role in the study design, data collection and analysis, decision for publication, or preparation of the manuscript. The authors have no conflicts of interest to disclose. Supplemental Digital Content..