A genome-wide association study (GWAS) identified two genetic loci associated with severe Covid-19 with respiratory failure. The study included 1980 patients with severe Covid-19 and 2381 control participants from Italy and Spain. After quality control, 835 patients and 1255 controls from Italy, and 775 patients and 950 controls from Spain were included. A total of 8,582,968 single-nucleotide polymorphisms (SNPs) were analyzed, and a meta-analysis of the two case-control panels was conducted. Two loci reached genome-wide significance: rs11385942 at 3p21.31 and rs657152 at 9q34.2. The rs11385942 variant was associated with an increased risk of severe Covid-19 with respiratory failure, with an odds ratio of 1.77 (95% CI, 1.48 to 2.11; P=1.15×10⁻¹⁰). The rs657152 variant was associated with an increased risk, with an odds ratio of 1.32 (95% CI, 1.20 to 1.47; P=4.95×10⁻⁸). The association signal at 9q34.2 coincided with the ABO blood group locus. Blood group A was associated with a higher risk of severe Covid-19 compared to other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10⁻⁴), while blood group O was associated with a protective effect (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10⁻⁵). The study identified a gene cluster at 3p21.31 as a genetic susceptibility locus for severe Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. The study also found that the risk allele of rs11385942 was more common in patients who required mechanical ventilation than in those who only needed oxygen supplementation. The study highlights the importance of genetic factors in the development of severe Covid-19 and provides insights into the potential role of the ABO blood group system in susceptibility to the disease. The findings suggest that genetic factors, including the ABO blood group system, may play a role in the severity of Covid-19.A genome-wide association study (GWAS) identified two genetic loci associated with severe Covid-19 with respiratory failure. The study included 1980 patients with severe Covid-19 and 2381 control participants from Italy and Spain. After quality control, 835 patients and 1255 controls from Italy, and 775 patients and 950 controls from Spain were included. A total of 8,582,968 single-nucleotide polymorphisms (SNPs) were analyzed, and a meta-analysis of the two case-control panels was conducted. Two loci reached genome-wide significance: rs11385942 at 3p21.31 and rs657152 at 9q34.2. The rs11385942 variant was associated with an increased risk of severe Covid-19 with respiratory failure, with an odds ratio of 1.77 (95% CI, 1.48 to 2.11; P=1.15×10⁻¹⁰). The rs657152 variant was associated with an increased risk, with an odds ratio of 1.32 (95% CI, 1.20 to 1.47; P=4.95×10⁻⁸). The association signal at 9q34.2 coincided with the ABO blood group locus. Blood group A was associated with a higher risk of severe Covid-19 compared to other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10⁻⁴), while blood group O was associated with a protective effect (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10⁻⁵). The study identified a gene cluster at 3p21.31 as a genetic susceptibility locus for severe Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. The study also found that the risk allele of rs11385942 was more common in patients who required mechanical ventilation than in those who only needed oxygen supplementation. The study highlights the importance of genetic factors in the development of severe Covid-19 and provides insights into the potential role of the ABO blood group system in susceptibility to the disease. The findings suggest that genetic factors, including the ABO blood group system, may play a role in the severity of Covid-19.