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Cytokine gene polymorphisms are known to be associated with functional differences in cytokine regulation and may affect host susceptibility to tuberculosis ( TB). Contacts are important group in developing tuberculosis infection and are 10-60 times more likely to develop TB than general population. The present study was carried out in patients with TB ( N = 176), their household contacts ( HHC; N = 155) from Free Chest TB Clinic PPM DOTS (1 TU) covering 500,000 population at Mahavir Hospital and Research Centre, Hyderabad, and healthy controls ( HC; N = 170) also included. The association of single-nucleotide polymorphisms ( SNPs) in the promoter region of TNF-α (−308 G/ A), IL-2 (−330 T/ G), IL-4 (−589 C/ T) and in exon region of TGF- β 1 (+869T/ C) genes was assessed by ARMS & PCR- RFLP using specific primers in the above-mentioned subjects. The differences in allelic or genotypic frequencies of TNF-α (−308 G/ A) between patients, their HHC and HC were not statistically significant ( P > 0.05). IL-2 (−330 T/ G) TG genotype was significantly different between patients, HHC compared to HC ( P < 0.002, OR-1.997, 95% CI-1.260-3.168, P < 0.03, OR-1.602, 955 CI-1.003-2.561). IL-4 (−589 C/ T) CC genotype was significantly different between patients and HC ( P < 0.03, OR-1.791, 95% CI-1.009-3.189) as well as between HHC and HC at P < 0.0001, OR-2.56, 95% CI-1.448-4.545. In addition, the TGF-β 1 (+869T/C) TC genotype was significantly associated with susceptibility to tuberculosis in patients when compared against HC( P < 0.0001, OR-3.416, 95% CI-2.063-5.670) and HHC ( P < 0.0001, OR-2.357, 95% CI-1.439-3.868), respectively. MDR analysis indicated that TT genotype of TGF-β1 with TT and CT genotypes of IL-4 showed high risk with GA, TT genotypes of TNF-α, IL-2, respectively. Our results suggest that IL-2 (-330T/G), IL-4 (-589 C/T) and TGF-β1 (+869 T/ C) gene polymorphisms may be associated with TB susceptibility. [ABSTRACT FROM AUTHOR]