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Background: COVID-19 has been associated with negative results in patients with A blood group and with a better evolution in O blood group individuals., Aim: Because the evidence regarding ABO blood groups and COVID was empirically not that clear in our country, we tested the association regarding COVID-19 and blood groups., Material and Methods: Adult patients were enrolled in this prospective, case-control, observational multicenter study. Patients with a confirmed diagnosis of COVID-19 were assigned to one of three groups based on the clinical presentation of the infection. Age, gender, ABO and Rh blood groups, body mass index, history of diabetes mellitus or high blood pressure, and smoking were recorded directly or from their clinical charts. ABO blood group was obtained from 5,000 blood donors (50% each gender). Atherothrombotic variables were compared with a nation-wide data collection., Results: A total of 2,416 patients with COVID-19 were included (women:39.6%; men:60.4%). There were no significant differences between cases and controls in terms of age. O blood group was the most frequently found in healthy donors and COVID-19 patients, but this blood group was significantly higher in COVID-19 patients vs. healthy donors. ABO blood group was not associated with the final health status in COVID-19 patients. Obesity, diabetes mellitus, hypertension and smoking were significantly more frequent among COVID-19 patients., Conclusion: The proposed protective effect of the O blood group in COVID-19 patients could not be reproduced in the Mexican population while some atherothrombotic risk factors had a significant effect on the clinical evolution., Competing Interests: Conflict of Interests None declared., (Copyright © 2021. Published by Elsevier Inc.)