The degradation of p53 by high-risk human papillomavirus (HR-HPV) E6 proteins is recognized as necessary for the immortalization of mammary epithelial cells and the progression of cancer. The HR-HPV type 16 E6 proteins exhibit numerous variants associated with different risk factors for the development of cervical cancer. Two variants of E6 proteins, D25E and L83V, are common in cervical carcinomas among Asian and European populations. In the present study, we compared the effect of two E6 variants on p53 degradation by a prototype E6 protein. We demonstrate that both the D25E and L83V variants downregulate p53 through a ubiquitin-proteasome pathway, and that the effect is very similar to that of the prototype E6 protein. The reduction in the p53 protein levels was induced through the ubiquitin-proteasome pathway via interaction with E6 proteins. The expression of p21 CIP1/WAF1, a downstream molecule of p53, was similarly reduced in both prototype and variant E6 protein-expressing cell lines, leading to aberrant G1/S cell cycle arrest. These results suggest that the natural variants, E6 D25E and L83V, similar to the prototype E6 protein, contribute to tumorigenesis by degrading p53.