This study aimed at evaluating the association and interaction among human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) genotypic polymorphism, smoking status and oral cancer risk in Taiwan. For this purpose, the well-known polymorphic variants of hOGG1, codon 326, was analyzed for its association with oral cancer susceptibility, and its joint effect with individual smoking habits on oral cancer susceptibility. In total, 620 patients with oral cancer and 620 healthy controls were recruited from the China Medical Hospital and genotyped. The results showed that the hOGG1 codon 326 genotypes were differently distributed between the oral cancer and control groups (p=0.0266), with the C allele of hOGG1 codon 326 being significantly (p=0.0046) more frequently found in cancer patients than in controls. We further analyzed the genetic-smoking joint effects on oral cancer risk and found an interaction between hOGG1 codon 326 genotypes and smoking status. The hOGG1 codon 326 CC genotype was associated with oral cancer risk only in the smoker group (p=0.0198), but not in the non-chewer group (p=0.8357). Our results provide evidence that the C allele of hOGG1 codon 326 may have a joint effect with smoking on the development of oral cancer.