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Objectives: A possible association between blood group systems (ABO and Rh) and coronavirus disease 2019 (COVID-19) severity has recently been investigated by various studies with conflicting results. However, due to variations in the prevalence of the ABO and Rh blood groups in different populations, their association with COVID-19 might be varied as well. Therefore, we conducted this study on Libyan participants to further investigate this association and make population-based data available to the worldwide scientific community., Methods: In this case-control study, ABO and Rh blood groups in 419 confirmed COVID-19 cases in Zawia, Libya, and 271 healthy controls were compared using descriptive statistics and χ 2 tests., Results: Blood group A was significantly more prevalent in patients with severe COVID-19 (64/125; 51.2%) than in patients with nonsevere COVID-19 (108/294, 36.7%) (P < .034), whereas the O blood group prevalence was higher in nonsevere COVID-19 cases (131/294, 44.5%) compared with severe cases (43/125, 34.4%) (P < .001)., Conclusions: The results showed a significant association between blood group A and the severity of COVID-19, whereas patients with blood group O showed a low risk of developing severe COVID-19 infection. No significant association was found between Rh and susceptibility/severity of the disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)