The DNA repair gene Ku70, an important caretaker of the overall genome stability, is thought to play a major role in the DNA double strand break repair system. It is known that defects in double strand break repair capacity can lead to irreversible genomic instability. However, the polymorphic variants of Ku70 and their association with oral cancer susceptibility has never been reported on. In this hospital-based case-control study, the association of Ku70 promoter T-991C (rs5751129), promoter G-57C (rs2267437), promoter A-31G (rs132770), and intron3 (rs132774) polymorphisms with oral cancer risk in a Taiwanese population was investigated. In total, 318 patients with oral cancer and 318 age- and gender-matched healthy controls recruited from the China Medical Hospital in Taiwan were genotyped. The results showed that there were significant differences between the oral cancer and control groups in the distribution of their genotypes (P=0.0031) and allelic frequency (P=0.0009) in the Ku70 promoter T-991C polymorphism. Individuals who carried at least one C allele (T/C or C/C) had a 2.15-fold increased risk of developing oral cancer compared to those who carried the T/T wild-type genotype (95% CI: 1.37-3.36). In the other three polymorphisms, there was no difference between both groups in the distribution of either genotype or allelic frequency. In conclusion, the Ku70 promoter T-991C, but not the Ku70 promoter C-57G, promoter A-31G or intron3, is connected to oral cancer susceptibility. This polymorphism may be a novel useful marker for primary prevention and anticancer intervention.