Analysis of gene-environment interactions may help to define the risk of oral leukoplakia. We hypothesized that an individual's susceptibility to leukoplakia is dependent on interactions between polymorphic genotypes at susceptible loci and tobacco exposure. To test this hypothesis, the relationship between tobacco use and polymorphisms in 3 genes that might contribute to variance in individuals' susceptibility to the risk of leukoplakia was determined. In this case-control study, polymorphic genotypes in XRCC1 (399Gln), a DNA repair gene involved in removing DNA adducts, CCND1 (G870A), a key component of cell cycle regulation, and GSTM1 (null genotype), a xenobiotic-metabolizing enzyme involved in the metabolism of tobacco carcinogens, were analyzed in 100 oral leukoplakia patients and age- and gender-matched controls by PCR using genomic DNA isolated from blood. The GSTM1 null genotype was associated with a 1.6-fold increased risk of developing leukoplakia. The risk conferred by the CCND1 GA+AA variant was 2.4-fold that of the GG genotype. Importantly, among non-users of tobacco, the XRCC1 (GA+AA) variant emerged as the most significant determinant of an individual's susceptibility to leukoplakia (OR=3.5). In GSTM1 null individuals, tobacco consumption increased the risk of leukoplakia 21.3-fold. Similarly, XRCC1 A allele carriers and CCND1 A allele carriers who consumed tobacco were at a significantly high risk of developing leukoplakia (OR=11.8 and 14.9, respectively). Our study provides evidence that tobacco use in individuals harboring these polymorphic genotypes elevates the risk of oral leukoplakia and warrants further studies on gene-environment interactions to define the risk of malignant transformation of leukoplakia.