Abstract: Background and Objective: Inherited polymorphisms in carcinogen metabolizing and DNA repair genes may contribute to variations in carcinogen metabolism and DNA repair capacity and thus genetic susceptibility to cancer. This study was performed to evaluate the association between polymorphism of two genes namely XPC and GSTT1 and risk for development of oral lesion. Materials and Methods: In a hospital-based case-control study a total of 46 histopathologically proven leukoplakia, erythroplakia, lichen planus and oral submucous fibrosis patients and equal number of age, sex, ethinicity and habit matched healthy control subjects were taken. Subjects were genotyped for XPC Intron 9 (Ins/Del) polymorphisms with allele specific PCR method: Whereas, XPC Exon 16 (A>C) polymorphism were genotyped by PCR-RFLP. For genotyping of GSTT1, multiplex PCR was used. The association between DNA damage response gene polymorphisms and oral lesion occurring risk was assessed by calculating odds ratios (OR) with 95% confidence intervals (CI). The combined ORs were calculated under the dominant genetic model for each polymorphism. All the statistical analyses were two sided and conducted using the EPIinfo software. Results: Overall, a significant association of XPC poly AT Del/Del (D/D) genotype with increase risk of oral lesion was observed. Similarly AA genotypes for XPC exon 16 variant presented statistically significant p<0.05 increased risk of oral lesions. In contrary, AC and CC genotypes from the same polymorphism found to be protective for the development of oral lesion with OR-0.387 and 0.174, respectively for AC and CC genotype. The study demonstrates that absence of GSTT1 gene increases the risk of developing oral lesions. Conclusion: The present study supports that polymorphism in XPC gene may reduce the risk of developing oral lesions in North Indian population, whereas GSTT1 null genotype increases the risk of oral lesions.