Immunity-related GTPase family M protein (IRGM) is a human protein recently highlighted for its contribution to autophagy upon infections. Evidences have shown that IRGM may also play critical roles in the pathogenesis of cancer. However, correlation between IRGM and glioma remains unclear. In the current study, we investigated two IRGM genetic polymorphisms, rs10065172C/T and rs13361189T/C, in glioma and their effects on cytokine expression. Data showed that prevalences of rs13361189TC genotype were significantly increased in glioma patients than in healthy controls (odds ratio (OR) = 1.53, 95 % confidence interval (CI) 1.05-2.24, P = 0.028), and frequency of polymorphic rs13361189CC genotype was further elevated (OR = 2.43, 95 % CI 1.43-4.14, P = 0.001). Interestingly, rs13361189TC and CC genotypes revealed a strong association with language impairment in glioma patients (OR = 2.16, P = 0.023; OR = 3.71, P = 0.001, respectively). When analyzing these two polymorphisms with related cytokine expression, we observed that subjects carrying rs13361189CC genotype had higher serum level of interferon-gamma (IFN-γ) than those with wild-type TT genotype (P < 0.01). In addition, subjects with rs13361189TC and CC genotypes presented elevated serum level of interleukin 4 (IL-4) than those with TT genotype. These data indicate a potential role of IRGM in the development of glioma probably by affecting IFN-γ and IL-4.