Like xeroderma pigmentosum (XP) patients, transgenic mice lacking nucleotide excision repair (NER) genes such as XPA and XPC are extremely susceptible to ultraviolet (UV)-induced skin cancer. Because the p53 gene is an important target for UV carcinogenesis and because the p53 protein modulates NER, we investigated the consequences of NER deficiency on UV-induced p53 mutations in XPC−/− mouse skin tumors. Thirty-eight (76%) of 50 UV-induced XPC−/− skin tumor analysed displayed C→ T or CC→ TT transitions at dipyrimidine sites on the untranscribed strand of the p53 gene. A major hot spot for p53 mutation occurred at codon 270, which is also a hot spot in UV-induced skin tumors from NER-proficient C3H and SKH-hr 1 mice. Interestingly, codon 270 mutations were induced in both XPC−/− and+/+ mouse skin after 1 week of UV irradiation, but the mutations persisted only in XPC−/− mouse skin after 3–4 weeks of chronic UV. The persistence of UV-induced p53 mutations in XPC−/− mouse skin was associated with decreased apoptosis and increased proliferation of keratinocytes, suggesting that these events may contribute to the accelerated development of UV-induced skin tumors in XPC−/− mice.