The aims of this study were to evaluate the genotype frequencies of p53 codon 72 and p21 codon 31 in cervical adenocarcinoma patients and controls, and the association between the specific genotype or genotype combination of these polymorphisms and the risk of cervical adenocarcinoma in Korean women. Genotyping was performed using DNA from cervical biopsy specimens collected from 53 patients with cervical adenocarcinoma, of whom 34 were HPV 16 or 18 positive, and from the cervical exfoliated cells from 286 control women, of whom 48 were positive for HPV 16 or 18. For the determination of p53 polymorphisms genomic DNA was examined by PCR amplification of the specific allele assay, and for the determination of p21 polymorphisms DNA was examined by the PCR-RFLP assay using BsmAI. We found significant differences in genotype frequencies of both genes between the two groups (p < 0.001). The p53 genotypes containing the Pro allele were significantly associated with cervical adenocarcinoma with an OR of 2.89 (95% CI 1.54-5.42). Also, homozygous carriers of the p21 Ser allele showed a substantially increased risk of developing cervical adenocarcinoma (OR 2.07; 95% CI 1.13-3.79) compared to genotypes containing the Arg allele. In addition, the combination of the Pro allele containing genotypes of p53 and the Ser homozygous genotype of p21 posed a remarkably increased risk (OR 5.22; 95% CI 2.24-12.16), although the interaction of the two genes could not be found. These significant differences were intensified in groups with high-risk HPV infection (types 16 or 18).