Interferon-gamma is the most important cytokine in resistance to mycobacterial diseases and common variants of interferon-gamma gene could be related to tuberculosis susceptibility. We tested the hypothesis that the interferon-gamma+874T-A polymorphism is associated with tuberculosis disease, and affects the interferon-gamma response. We determined by pyrosequencing the distribution of the interferon-gamma+874T-A polymorphism in a Turkish population of 319 patients with pulmonary tuberculosis, 42 children with severe forms of tuberculosis and 115 healthy donors. We also analysed whether any correlation exists between this polymorphism and interferon-gamma response to Mycobacterium tuberculosis antigens by ELISPOT in 58 pulmonary tuberculosis cases, and the results were analysed according to the genotypes. We found that the minor allele (T) frequency was significantly lower in patients with pulmonary tuberculosis when compared to controls (P=0.024, OR=0.7), a similarly significant decrease in the frequency of TT genotype was observed in patients with pulmonary tuberculosis, compared to the control group (P=0.02, OR=0.49). IFN-gamma responses to PPD antigen in TT genotype was found to be significantly higher than the AA group (P>0.001). Non-parametric correlation analysis of ELISPOT data showed significant reverse correlation in PPD, CFP10 and ESAT6 values and IFN-gamma +874 genotypes. These results show that the IFN-gamma +874T-A polymorphism is related to the IFN-gamma response and the magnitude of the response decreases during transition from TT- to TA and to AA genotypes. Our data suggest that similar to various Caucasian populations, in a Turkish population the IFN-gamma+874 T-A polymorphism is also associated with tuberculosis disease and affects the magnitude of the IFN-gamma response.