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Host genetic single nucleotide polymorphisms can exert an influence susceptibility to tuberculosis infection. Previous investigations have demonstrated an association between the polymorphism in the ALOX5 gene and a range of diseases, encompassing not only noninfectious conditions like asthma, acute myocardial infarction, and cerebral infarction but also infections caused by various pathogens. However, the relationship between ALOX5 gene polymorphism and susceptibility to tuberculosis has received limited research attention. The ALOX5 gene encodes arachidonic acid 5-lipoxygenase(5-LO), which serves as the initiating catalyst in the generation of the inflammatory mediator leukotriene. Leukotrienes, products derived from the 5-LO pathway, are potent proinflammatory lipid mediators that assume a pivotal role in tuberculosis infections.Consequently, ALOX5 gene variants may be intricately associated with the pathogenesis of tuberculosis. In instances where the host exhibits immunocompromisation, infection with Mycobacterium tuberculosis can impact multiple systems. The involvement of multiple systems significantly augments the complexity of treatment and escalates patient mortality rates. Regrettably, the underlying mechanisms driving multisystem tuberculosis pathogenesis remain enigmatic, with clinicians paying scant attention to this aspect. Although the protein encoded by the ALOX5 gene represents a pivotal enzyme that catalyzes the metabolism of arachidonic acid into LXA4, and thereby plays a significant role in the inflammatory response during tuberculosis infection, studies investigating ALOX5 gene polymorphism and its association with susceptibility to multisystem tuberculosis in the Chinese Han population are exceptionally scarce. Therefore, the primary objective of this study is to comprehensively examine the correlation between ALOX5 gene polymorphisms and susceptibility to tuberculosis within the Chinese Han population, with particular emphasis on multisystemic tuberculosis. A case‒control study design was employed, encompassing 382 individuals with pulmonary tuberculosis and 367 individuals with multisystemic tuberculosis as the case groups, along with 577 healthy controls.Whole blood DNA was extracted from all patients and healthy controls. Subsequently, three tag polymorphisms (rs2029253, rs7896431, rs2115819) within the ALOX5 gene were selectively identified and genotyped. After adjusting for age and sex, the presence of allele A at rs2029253 exhibited a pronounced association with an elevated risk of TB susceptibility when compared to the tuberculosis group and healthy control group. (ORa: 2.174, 95% CI: 1.827–2.587; Pa<0.001, respectively). Notably, the rs2029253 AG genotype and AA genotype displayed a significantly increased susceptibility to tuberculosis (ORa: 2.236, 95% CI: 1.769–2.825; Pa <0.001 and ORa: 4.577, 95% CI: 2.950–7.100; Pa <0.001, respectively) compared to the GG genotype. Moreover, in the analysis utilizing genetic models, rs2029253 also exhibited a markedly heightened susceptibility to tuberculosis in additive models, dominant models, and recessive models (Pa <0.001). Conversely, no significant association was observed between rs7896431, rs2115819, and tuberculosis. In the subgroup analysis, when comparing the pulmonary tuberculosis group with the healthy control group, we observed no significant disparities in the distribution frequencies of alleles, genotypes, and gene models (additive model, dominant model, and recessive model) for the three tag SNPs, with P-values were >0.05 after adjusting for age and sex. Additionally, we noted that the presence of allele A at rs2029253 was linked to an increased susceptibility to tuberculosis in the multisystemic tuberculosis group relative to the healthy control group (ORa: 2.292, 95% CI: 1.870–2.810; Pa<0.001). Similarly, the rs2029253 AG genotype, AA genotype, and gene models, including the additive model, dominant model, and recessive model, demonstrated a significantly elevated risk of tuberculosis susceptibility. The polymorphism in the ALOX5 gene is associated with susceptibility to multisystemic tuberculosis in the Chinese Han population. • ALOX5 SNP is associated with multisystemic TB susceptibility. • rs2029253 was associated with an increased risk of multisystemic TB infection. • ALOX5 SNP may not be associated with the susceptibility to pulmonary TB. • The study population was the Chinese Han population. [ABSTRACT FROM AUTHOR]