Abstract Background In the current study we aimed to find out the impact of cytokine-inducible Src homology 2 domain protein (CISH) gene polymorphisms on the risk of pulmonary tuberculosis (PTB) in a sample of Iranian population. Materials and methods Polymorphisms of CISH rs2239751, rs414171, and rs6768300 were determined in 200 PTB patients and 200 healthy subjects using T-ARMS-PCR or PCR-RFLP method. Results The results showed that rs414171 A>T genotypes significantly decreased the risk of PTB (OR = 0.16, 95% CI = 0.10–0.27, p < 0.0001, AT vs AA; OR = 0.31, 95% CI = 0.14–0.68, p < 0.0001, TT vs AA; OR = 0.19, 95% CI = 0.12–0.29, p < 0.0001, AT+TT vs AA; OR = 0.29, 95%CI = 0.20–0.42, p < 0.0001, T vs A). For rs6768300, the findings indicated that this variant decreased the risk of PTB (OR = 0.52, 95% CI = 0.33–0.82, p = 0.005, CG vs GG; OR = 0.57, 95% CI = 0.38–0.87, p = 0.012, C vs G). No significant association was observed between CISH rs2239751 polymorphism and risk/protection of PTB. Conclusion Our findings indicated that CISH rs414171 and rs6768300 variants might be associated with protection from PTB.