The DNA repair gene ERCC6, an important caretaker of the overall genome stability, is thought to play a role in the development of human malignancy. However, the polymorphic variants of ERCC6, has never been reported about their association with oral cancer susceptibility. In this hospital-based case-control study, the association of ERCC6 codon 399, 1097 and 1413 polymorphisms with oral cancer risk in a Central Taiwanese population was first investigated. In total, 292 patients with oral cancer and 290 age- and gender-matched healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. We found a significant different distribution in the frequency of the ERCC6 codon 399 genotypes, but not the ERCC6 codon 1097 or 1413 genotypes, between the oral cancer and control groups. Those who had homozygous A/A or heterozygous A/G at ERCC6 codon 399 showed a 1.82- and 1.22-fold (95% confidence interval=1.19-2.79 and 0.83-1.78, respectively) increased risk of oral cancer compared to those with G/G. As for ERCC6 codon 1097 or 1413, there was no difference in distribution between the oral cancer and control groups. Gene-environment interactions with smoking and betel quid chewing, but not alcohol drinking, were significant for ERCC6 polymorphisms. ERCC6 codon 399, G/A+A/A ever user groups exhibited an increased risk of 2.36 (95% CI=1.36-4.10) for smoking and 2.72 (95% CI=1.31-5.63) for betel quid chewing. Our results firstly suggest that the heterozygous and homozygous A allele of the ERCC6 codon 399 may be associated with the development of oral cancer and may be a novel useful marker for primary prevention and anticancer intervention.