Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. IRGM1 is an important protein in the innate immune response against intracellular pathogens by regulating autophagy. Polymorphisms in the IRGM genes are known to influence expression levels and may be associated with outcome of infections. This case-control study was done on 150 patients with PTB and 150 healthy subjects to determine whether the IRGM polymorphisms at positions -1208 A/G (rs4958842), -1161 C/T (rs4958843), and -947 C/T (rs4958846) were associated with PTB. The polymorphisms were determined using tetra-amplification refractory mutation system-PCR (T-ARMS-PCR). The results showed that the IRGM -1161 C/T and -947 C/T polymorphisms were associated with decreased susceptibility to PTB (OR = 0.06, 95% CI = 0.03-0.13, P < 0.001 and OR = 0.27; 95% CI = 0.013-0.55, P < 0.001, resp.). No significant difference was found among the groups regarding -1208 A/G polymorphism. In conclusion we found that the IRGM -1161 C/T and -947 C/T polymorphisms but not -1208 A/G polymorphism provide relative protection against PTB in a sample of Iranian population.