Xeroderma pigmentosum (XP) is an inheritable disease characterized by sun-sensitivity and a high frequency of skin cancers including melanoma. We have analyzed two different groups of XP: the XP complementation group C (XP-C), deficient in global nucleotide excision repair but proficient in transcription-coupled repair and associated with a very early onset of skin cancers; and the XP variant (XPV), deficient in the bypass of DNA photoproducts. To get new insights into the biology of melanoma in XP patients, we studied 20 melanomas from four XP-C and two XPV patients in terms of pathology, immunohistochemistry of p53, mutations in exons 4-9 of the p53 gene, and polymorphisms of the p53 gene at codon 72. All statistical tests were two-sided. The majority of the XP melanomas were of the lentigo maligna melanoma (LMM) type, as found in the elderly. p53 point mutations were found in 60% of XP-C melanomas and in only 10% of XPV melanomas, this latter frequency being similar to what has been reported in the general population. Mutations show the specific UV-signature because the majority were CC to tandem and C to T transitions located at the bipyrimidine sites known to be hotspots of UV-induced DNA lesions. All DNA lesions giving rise to mutations in XP-C melanomas were located on the nontranscribed strand of the p53 gene, demonstrating that these patients' cells were able to carry out preferential repair in vivo. The LMMs found in XP-C are associated with an accumulation of unrepaired DNA lesions and may represent a good model for the LMM induction in the elderly.