Abstract: OBJECTIVE To analyze the association of septic shock with polymorphisms of interleukin receptor-1-related kinase-M (IRAKM) and interleukin-1 receptor α (IL-1Rα) genes. METHODS A total of 81 patients with septic shock admitted to Wuhan First Hospital between Jan. 2020 and Mar. 2022 were selected as the study group, and 85 sepsis patients without septic shock were selected as control group, in which patients with septic shock were divided into the death group and the survival group according to 28 d death status. The polymorphisms of IRAKM and IL-1Rα (IL-1RN) genes in peripheral blood were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR. The above genotypes in each group were compared, and their relationship with acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA) scores and stay time in intensive care unit (ICU) was analyzed. RESULTS The frequencies of GG genotype and G allele at IRAKM+22148 locus, and frequencies of IL-1RN*1,2 genotype and allele 2 in the study group were higher than those in the control group (P<0.05). GG genotype and G allele at IRAKM+22148 locus, IL-1RN*1,2 genotype and allele 2 were risk factors for the occurrence of septic shock (P<0.05). The frequency of G allele at IRAKM+22148 locus in death group was higher than that in survival group (P<0.05), which was a risk factor for sickness and death in patients with septic shock (P<0.05). APACHE II and SOFA scores, CRP and PCT levels in patients with GG genotype at IRAKM+22148 locus were higher than those with AA and AG genotypes (P<0.05). SOFA score, CRP and PCT levels in patients with IL-1RN*1, 2 genotype were higher than those with 1, 1 type and the other genotypes (P<0.05). CONCLUSION The G allele at IRAKM+22148 locus and IL-1RN allele 2 were closely related to the susceptibility of septic shock, which also increased the risk of poor prognosis in patients.