DNA repair capacity is essential in maintaining cellular functions and homeostasis. However, the repair capacity can be altered based on DNA sequence variations in DNA repair genes and thus may cause cancer susceptibility. We investigated associations between polymorphisms in DNA repair genes and oral squamous cell carcinoma (OSCC) in a Thai population. Nine known single nucleotide polymorphisms (SNPs) in five common DNA repair genes were investigated: XRCC1 (Arg194Trp and Arg399Gln); XRCC3 (Thr241Met); XPC (PAT and Lys939Gln); XPD (exon 6, and Lys751Gln); and MGMT (Trp65Cys and Leu84Phe). We studied 106 cases and 164 healthy controls that were frequency-matched by age (+/-5 years), gender, and cigarette smoking and alcohol drinking habits. The genotype assays were performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The R version 2.0.1 statistical software was applied for statistical analysis of association. Based on multivariate analyses, we found that the variant genotypes with XRCC3 241Met exhibited a >3-fold elevated risk (OR = 3.3, 95% CI = 1.31-8.36, p = 0.01) for OSCC. There was a marginally significant risk observed in variants with XRCC1 194Trp (OR = 1.81, 95% CI = 0.91-3.63, p = 0.09) and XPD exon 6 (OR = 1.71, 95% CI = 0.93-3.16, p = 0.09). Combination of the variant genotypes of these three susceptibility genes was associated with a highly significant risk for OSCC (OR = 9.43, 95% CI = 1.98-44.9, p < 0.01). From further multivariate analyses, the variants with XRCC1 194Trp and possibly XRCC3 241Met interacted with tobacco and alcohol to further increase the risk (OR = 3.37 95% CI = 1.41-8.02, p < 0.01; OR = 2.92, 95% CI = 0.94-9.04, p = 0.06). On the other hand, increased risk was detected in non-betel chewers (OR = 2.88, 95% CI = 1.31-6.31, p < 0.01; OR = 2.61, 95% CI = 0.97-7.11, p = 0.06) who carry the two variant genotypes, respectively. Males with the variants XRCC1 194Trp or XRCC3 241Met had a higher risk of developing OSCC than males with the corresponding wild-type genotypes (OR = 2.72, 95% CI = 1.34-5.52, p < 0.01; OR = 2.95, 95% CI = 1.12-7.75, p < 0.05). Such association was not detected in females. Interestingly, the risk increased in female carriers of XPD exon 6 (OR = 3.93, 95% CI = 1.14-13.6, p < 0.05). We could not demonstrate a significant interaction of these SNPs with age in this study. Our data indicate that the variant genotypes with XRCC3 241Met and possibly XRCC1 194Trp and XPD exon 6 contribute to OSCC development in a Thai population. In addition, these SNPs influence the repair of DNA damage that is caused by environmental risk factors for oral cancer.