Oral premalignant lesions (OPLs) are early genetic events en route to oral cancer. To identify individuals susceptible to OPL is critical to the prevention of oral cancer. In a case-control study consisting of 147 patients with histologically confirmed OPL and 147 matched controls, we evaluated the associations of 10 genetic variants in nine genes of the double-strand break (DSB) DNA repair pathway with OPL risk. The most notable finding was an intronic polymorphism (A17893G) of the XRCC3 gene. Compared with the homozygous wild-type AA genotype, the odds ratio (OR) (95% confidence interval [CI]) for the heterozygous AG and homozygous variant GG genotype was 0.85 (0.49-1.48) and 0.18 (0.07-0.47), respectively (P for trend=0.002). In addition, compared with the most common A-C haplotypes of XRCC3 (in the order of A17893G-T241M), the G-C haplotypes were associated with a significantly decreased risk of OPL (OR=0.40, 95% CI 0.23-0.68). Moreover, compared with individuals without the G-C haplotype, the OR was 1.04 (0.56-1.95) and 0.20 (0.08-0.51) for subjects with one copy and two copies of the G-C haplotypes, respectively (P for trend=0.005). Classification and regression tree (CART) analysis further revealed potential high-order gene-gene and gene-environmental interactions and categorised subjects into different risk groups according to their specific polymorphic signatures. Overall, our study provides the first epidemiological evidence supporting a connection between DSB gene variants and OPL development. Our data also suggest that the effects of high-order interactions should be taken into consideration when evaluating OPL predisposition.