•SNPs at promoter directly affect the cytokine production.•Leprosy progression is associated with high producer genotypes of IL-10 and TNFα.•IL-10−1082 GG masks the production of high producer genotype of TNFα in leprosy.•TNFα−308GG, IL-10−819TT is predominant genotypes in our studied patients.•Individuals with these genotypes and IL-10−1082 GG are susceptible to leprosy. Leprosy is an infectious disease caused by M. leprae. We analyzed 48 cytokine polymorphisms in 13 (pro as well as anti-inflammatory) cytokine genes using PCR-SSP assay in 102 leprosy patients and 120 healthy controls with intent to find out a link between cytokine polymorphisms and disease susceptibility. TNF-α (−308) GG, IL-10 (−819) TT, IL-10 (−1082) GG and IL1R (+1970) CC genotypes are found to be predominant (p=0.01, p=0.02, p=0.0001 and p=0.001, respectively) in both tuberculoid as well as lepromatous leprosy patients. This observation suggests these genotypes as play the central role(s) in the progression of disease. CBA assay demonstrates the varied serum concentration of these cytokines with respect to their genotypes. The above genotypes appeared as high producer genotypes in our study. Even in presence of high produce genotypes, TNF-α level are found to be affected/masked by the presence of IL-10 in leprosy patients. Expressional masking of TNF-α is associated with the expression of IL-10 in these patients. This is one the negative impact of SNP–SNP interaction in leprosy patients. Therefore, we can conclude that cytokine gene polymorphisms determine the predisposition to the leprosy progression.