Background/Aim: Xeroderma pigmentosum complementation group C (XPC) is reported to play important roles in DNA integrity and genomic instability, however, the contribution of XPC to oral carcinogenesis is largely uncertain. Therefore, we aimed at examining the contribution of XPC genotypes to oral cancer. Materials and Methods: The genotypes of XPC rs2228001 and rs2228000 were examined among 958 oral cancer patients and 958 control subjects by polymerase chain reaction-restriction fragment length polymorphism methodology and corresponding DNA repair capacity was checked. Results: First, the percentages of XPC rs2228001 AC and CC were higher among oral cancer patients than controls. Second, no significant association was observed regarding XPC rs2228000. Third, there was a synergistic influence of smoking and betel quid chewing behaviors and XPC rs2228001 genotype on oral cancer risk. Last, functional experiments showed DNA repair capacity was lower for AC/CC carriers than AA carriers. Conclusion: XPC rs2228001 C allele, which was associated with decreased DNA repair capacity, may interact with smoking and betel quid chewing behaviors on oral cancer risk.Oral cancer is the tenth most common cancer worldwide, and Taiwan has one of the highest incidences (1). Based on the most updated annual statistics from the government, oral cancer is of the fourth death-causing cancers among Taiwanese males (2). Uniquely, betel quid chewing, in addition to cigarrete smoking and alcohol drinking, has been identified as an effective environmental factor to oral cancer risk in Taiwan (3). The Taiwan government has embarked in population screen searching for the oral cancer candidates for early cure and medication to lower its incidence, however, the death rate and incidence of oral cancer were still high. Therefore, novel predictors for oral cancer risk are still needed.There are five major DNA repair systems, consisting of more than 130 genes, and teaming up to maintain the stability and integrity of the human genome. Among them, the nucleotide excision repair (NER) system is in charge of removing DNA crosslinks, bulky adducts, alkylating DNA adducts, oxidative DNA adducts and thymidine dimers (4-6). In NER machinery, four major steps (adduct recognition, lesion DNA incision, gapped DNA fulfilling and ligation) and several core players, including xeroderma pigmentosum complementation group C (XPC)-RAD23B, play critical roles as key enzymes (4, 5) Theoretically, subtle genetic 441 This article is freely accessible online.