In immunocompromised patients, cooperative effects of human papillomavirus (HPV) and ultraviolet (UV) radiation have been postulated in the development of non-melanoma skin cancers. The tumor suppressor p53 is a key component of the cellular response to genotoxic agents, such as UV radiation. We have previously demonstrated that in HPV16-infected cells, a higher E6* level was associated with a higher resistance to UV and oxidative stress. Using the two same SKv cell lines, the aim of the present study was to investigate p53 and p21 expression and cell death in HPV-infected keratinocytes in response to UV irradiation and to determine the role of HPV oncoprotein levels on the p53-mediated cellular response. We demonstrated that the weakly E6*-expressing level SKv-e cell line presented both higher cytotoxicity and apoptosis to UV. This high sensitivity was associated with both p53 and p21 nuclear accumulation, while a high E6* level and resistance were associated with no p53 accumulation and a p21 nuclear down-regulation after UV. Moreover, in SKv-e cell line, p21 promoter activation was p53 dependent. Our results suggest that an alteration and/or a modulation of the p53-p21 pathway in response to UV could be determinant for HPV-infected keratinocyte survival and HPV-associated carcinogenic process.