Background Interleukin-18 (IL-18) and interferon-γ (IFN-γ) are cytokines of crucial role in inflammation and immune reactions. There is a growing evidence supporting important roles for IL-18 and IFN γ in tuberculosis (TB) infection and anti-tuberculosis immunity. Objective To evaluate the role of polymorphisms in IL-18-607 and -137 and INF-γ +874 in susceptibility to TB infection among Egyptian patients. Methods A case control study was conducted to investigate the polymorphism at IL-18-607, -137 and INF-γ+874 by sequence specific primer-polymerase chain reaction (SSP- PCR) in 105 patients with pulmonary and extra pulmonary tuberculosis and 106 controls. Results A significant protective effect against TB was found in homozygous CC genotype at IL-18 -137G/C, in addition to a 7-fold risk with GG and GC genotypes in the recessive model. Apart from a decreased risk with the AC genotype, no association was detected between the susceptibility to TB and different genotypes or alleles at the IL-18 -607A/C site. The homozygous AA genotype in INF-γ+874 showed a significant higher risk to TB than the homozygous TT or heterozygous AT genotypes with nearly a 2-fold risk of TB infection with the A allele. Regarding haplotype association, the GC haplotype was strongly associated with TB infection compared to other haplotypes. Conclusion These findings suggest; for the first time in Egypt; a significant risk to TB infection with SNP at the IL-18-137G/C with no LD with SNP at the IL-18-607 site. The homozygous AA genotype in INF-γ+874 showed a significant higher risk to TB than the homozygous TT or heterozygous AT genotypes.