While many p53-deficient cell types are impaired in global genomic nucleotide excision repair of cyclobutane pyrimidine dimers (CPDs), human epidermal keratinocytes expressing human papillomavirus type 16 E6 and E7 are p53 deficient and yet maintain repair of CPD. We hypothesized that the p53 homolog, p63, may participate in governing global repair instead of p53 in keratinocytes. Following ultraviolet radiation (UVR) of E6/E7 keratinocytes, depletion of p63 but not of p73 impaired global genomic repair of CPD relative to control cells. In all cases, repair of pyrimidine(6-4)pyrimidone photoproducts, the other major UVR-induced DNA lesions, was unaffected. In E6/E7 keratinocytes treated with p63 small interfering RNA, reduced global repair of CPD was associated not with reduced levels of messenger RNA-encoding DNA damage recognition proteins but rather with decreased levels of DDB2 and XPC proteins, suggesting that p63 posttranscriptionally regulates levels of these proteins. These results indicate that global repair may be regulated at multiple levels and suggest a novel role for p63 in modulating repair of DNA damage in human keratinocytes. The results may provide insight into mechanisms of genomic stability in epithelia infected with oncogenic human papilloma viruses and may further explain the lack of increased skin cancer incidence in Li-Fraumeni syndrome.