Background: Pakistan ranks 7th globally in terms of tuberculosis (TB) disease burden (incidence 181/100000 pop./yr; prevalence of 329/pop./ yr). Reports from different populations show variable associations of TB susceptibility and severity with cytokine gene polymorphisms. Tuberculosis clinical severity is multi-factorial and cytokines play a pivotal role in the modulation of disease severity. We have recently reported that the ratio of two key cytokines (IFNγ and IL10) show significant correlation with the severity spectrum of tuberculosis. The objective of the current study was to analyze the frequency of cytokine gene polymorphisms linked to high and low responder phenotypes (IFNγ +874 Thi→Alo and IL10 - 1082 Glo→Ahi) in tuberculosis patients. Methods and Findings: Study groups were stratified according to disease site as well as disease severity: Pulmonary N = 111 (Minimal, PMN = 19; Moderate, PMD= 63; Advance, PAD = 29); Extra-pulmonary N = 67 (Disseminated DTB = 20, Localized LTB = 47) and compared with healthy controls (TBNA = 188). Genotype analyses were carried out using amplification refractory mutation system-PCR (ARMS-PCR) and stimulated whole blood (WB) culture assay was used for assessing cytokine profiles. Our results suggest that the IFNγ +874 TT genotype and T allele was overrepresented in PMN (p = 0.01) and PMD (p = 0.02). IFNγ +874 TT in combination with IL10 GGlo genotypes showed the highest association (χ2 = 6.66, OR = 6.06, 95% CI = 1.31-28.07, p = 0.01). IFNγ AAlo on the other hand in combination with IL10 GGlo increased the risk of PAD (OR = 5.26; p = 0.005) and DTB (OR = 3.59; p = 0.045). Conclusion: These findings are consistent with the role of IL10 in reducing collateral tissue damage and the protective role of IFNγ in limiting disease in the lung.