Among those developing tuberculosis (TB) after exposure to Mycobacterium tuberculosis, approximately 70% are males. Host genetic variation, particularly immune-related genes on the X chromosome, may contribute to sex-specific differences in TB incidences. To study whether X-linked gene variation is associated with sex-specific presentation of pulmonary TB (pTB), three single-nucleotide polymorphisms (SNPs) of the TLR8, CD40LG and IRAK1 genes on the X chromosome were genotyped in 923 patients and 1033 healthy individuals of the Han Chinese population. Frequencies of the variants were analyzed independently as well as in their combinations. CD40LG rs3092923 and its combined effects with the other two SNPs were associated with an increased risk of pTB only in males. In males, the rs3092923 genotype C/(-) conferred relative protection (odds ratio (OR): 0.52, 95% confidence interval (CI): 0.35-0.78, Pcorr.=0.0045) and the combined effects of three SNPs increased gradually as the number of risk alleles increased (OR: 2.58, 2.83 and 2.96 for one, two and three risk alleles, respectively). For the remaining SNPs, significance was obtained only for the AA genotype of IRAK1 rs3027898 in the combined and female-only analysis. Our results indicate a role of a CD40LG variant and its combined effects with distinct TLR8 and IRAK1 variants in susceptibility to pTB in males.