We have investigated UV-B-induced skin tumors of hairless SKH-HRA mice for alterations in the p53 gene and for mutations in either of the three ras genes. Out of 32 tumors screened, only one contained a ras mutation, i.e. in codon 12 of the K-ras gene. Alterations in the p53 gene were much more abundant, as illustrated immunohistochemically by the accumulation of p53 protein in 75% of the tumor sections examined. Immunoreactivity was observed primarily in the proliferative cell compartment, but no clear correlation between p53 staining in tumor cells and histological parameters for malignancy was observed. Subsequent sequence analysis showed that point mutations in the p53 gene are detectable in 30% (nine out of 30) of the skin tumors examined. The majority of the mutations are located in codons 267 and 272, most likely originating from UV-B-induced photo-adducts at dipyrimidine sites in the non-transcribed strand. Codon 272 corresponds to the human codon 278, which is also a hotspot for p53 mutations in human non-melanoma skin cancers. Codon 267 matches the human codon 273, which does not contain a dipyrimidine site, but represents a CpG hotspot for p53 mutations in internal malignancies. Our results demonstrate that this hairless mouse model for UV-induced skin cancer corresponds closely to human non-melanoma skin cancers with respect to mutations in the p53 gene.