Human immunity-related GTPase M (IRGM) is found to play an important role in defense against intracellular pathogen Mycobacterium tuberculosis (M. tuberculosis) in vitro by regulating autophagy. The objective of the study was to determine the association between IRGM polymorphisms and susceptibility to pulmonary tuberculosis (PTB) in Chinese Hubei Han population. In this study, 237 PTB patients and 269 healthy controls were screened for IRGM promoter single nucleotide polymorphisms (SNPs) by gene sequencing, and an association study was performed. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The relative expression level of IRGM gene was measured by Real time Quantitative PCR (qRT-PCR). We identified 3 polymorphisms [-1208 (rs4958842), -1161 (rs4958843), and −947 (rs4958846)] in the IRGM promoter region. Our finding showed that the IRGM -947 CT genotype as well as CC genotype decreased the risk of PTB in comparison with TT genotype (OR = 0.216, 95% CI = 0.141–0.331,P < 0.001 and OR = 0.167, 95% CI = 0.088–0.318, P < 0.001,respectively). The −947C allele decreased the risk of PTB in comparison with T allele (OR = 0.266, 95% CI = 0.196–0.362, P < 0.001). There was linkage disequilibrium between these three IRGM SNPs and we further analyzed the haplotypes of these SNPs. Six haplotypes were identified and we found that the haplotype ACC played a protective role in the susceptibility to PTB. In contrast, the ACT haplotype was associated with an increased susceptibility to PTB. In addition, the ACT haplotype reduced the relative luciferase activity of IRGM promoter and decreased the expression of IRGM in PTB patients. Our findings indicated that IRGM functional polymorphisms and haplotypes in promoter were associated with the susceptibility to PTB in Chinese Hubei Han population.