Background: The tumor suppressor gene p53 and its downstream effector p21(CDKN1A/WAF1/CIP1) are thought to play major roles in the development of human malignancy. Polymorphic variants of p53, at codon 72, and CDKN1A, at codon 31, have been associated with cancer susceptibility, but few studies have investigated their effect on oral cancer risk. Materials and Methods: In this hospital-based case-control study, the association of p53 codon 72 and CDKN1A codon 31 polymorphisms with oral cancer risk in a Taiwanese population were investigated. In total, 137 patients with oral cancer and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. Results: We found a significant difference in the frequency of the p53 genotype, but not the CDKN1A genotype, between the oral cancer and control groups. Those who had Arg/Arg at p53 codon 72 showed a 2.68-fold (95% confidence interval=1.19-6.01) increased risk of oral cancer compared to those with Pro/Pro. The distribution of the combination of p53 codon 72 and CDKN1A codon 31 was different in the oral cancer and control groups. The percentages of three subgroups with the p53 GG homozygote were all higher in the oral cancer group, and the risky double homozygote, p53/CDKN1A GG/CC form, was almost 9-fold higher than the control group. Conclusion: Our findings suggest that the homozygous Arg allele of the p53 codon 72 may be associated with the development of oral cancer and be a useful marker for primary prevention and anticancer intervention.