This study conducted a genomewide association study (GWAS) to identify genetic factors associated with severe Covid-19 with respiratory failure. The study included 1980 patients with severe Covid-19 and respiratory failure from seven hospitals in Italy and Spain, along with 2381 control participants. After quality control, 835 patients and 1255 control participants from Italy, and 775 patients and 950 control participants from Spain were included in the final analysis. The study analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and performed a meta-analysis of the two case-control panels. Two loci, rs11385942 at locus 3p21.31 and rs657152 at locus 9q34.2, showed significant associations with severe Covid-19 with respiratory failure (P<5×10⁻⁸). The association signal at locus 3p21.31 spanned six genes, including SLC6A20, LZTFL1, CCR9, FICO1, CXCR6, and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus, with a higher risk in blood group A and a protective effect in blood group O. The study concluded that the 3p21.31 gene cluster is a genetic susceptibility locus for severe Covid-19 with respiratory failure, and the ABO blood group system is also involved.This study conducted a genomewide association study (GWAS) to identify genetic factors associated with severe Covid-19 with respiratory failure. The study included 1980 patients with severe Covid-19 and respiratory failure from seven hospitals in Italy and Spain, along with 2381 control participants. After quality control, 835 patients and 1255 control participants from Italy, and 775 patients and 950 control participants from Spain were included in the final analysis. The study analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and performed a meta-analysis of the two case-control panels. Two loci, rs11385942 at locus 3p21.31 and rs657152 at locus 9q34.2, showed significant associations with severe Covid-19 with respiratory failure (P<5×10⁻⁸). The association signal at locus 3p21.31 spanned six genes, including SLC6A20, LZTFL1, CCR9, FICO1, CXCR6, and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus, with a higher risk in blood group A and a protective effect in blood group O. The study concluded that the 3p21.31 gene cluster is a genetic susceptibility locus for severe Covid-19 with respiratory failure, and the ABO blood group system is also involved.