Glioma is one of the most common and lethal brain tumors. N-myc (and STAT) interactor (NMI) gene has been reported in tumorigenesis, and our previous study further showed its implication in glioma progression. To elucidate its involvement in the etiology of glioma, we conducted a case-control study of 875 patients and 1040 controls in a Chinese Han population by genotyping 7 representative single nucleotide polymorphisms (SNPs) in NMI. Allele and genotype frequency distribution of five loci (rs2278089, rs2194492, rs6734376, rs3854012, and rs11730) were significantly different between the cases and controls. Unconditional logistic regression showed that the variant genotypes of rs2278089 [adjusted odds ratio (OR) = 1.57, P = 4.23 × 10(-6)], rs2194492 (adjusted OR = 1.49, P = 1.20 × 10(-4)), and rs6734376 (adjusted OR = 0.06, P = 8.65 × 10(-13)) significantly affected glioma risk compared with the major homozygotes, while the minor homozygotes of rs3854012 (adjusted OR = 0.54, P = 4.64 × 10(-6)) and rs11730 (adjusted OR = 0.60, P = 1.50 × 10(-4)) showed significant protective effects. Further stratified analyses indicated that these associations remained significant in subgroups of low-grade glioma (LGG) and high-grade glioma (HGG). Additionally, haplotype and diplotype analyses showed consistent results. The Bonferroni correction was applied for all these analyses. Moreover, luciferase reporter gene assays revealed enhanced promoter activity of the C risk allele of rs2194492 in several cell lines compared with the G major allele, suggesting its potential function in transcriptional activation of NMI. Taken together, these results revealed that NMI polymorphisms may contribute to genetic susceptibility to glioma.