Simple SummaryXeroderma pigmentosum (XP) is a genetic disease caused by DNA repair deficiency. We diagnosed 181 XP patients from 1982 to 2022 in France. The patients are very sensitive to sunlight and will rapidly develop skin cancers in exposed body sites. However, thanks to better protection, XP patients live much longer than in the past. This better survival is associated, for the French XP patients originating from North Africa and bearing the same founder mutation in theXPCgene, with a very high risk to develop aggressive and lethal internal cancers, particularly hematological malignancies, and brain, gynecological, and thyroid tumors. This is a new threat hanging over all XP-C patients. The molecular origins of internal tumors in this particular set of DNA repair-deficient patients are discussed. It is important that physicians and XP families be aware of this high risk to prevent and look for early diagnosis of internal tumor development in XP patients.AbstractBackground: Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by a high incidence of skin cancers. These patients are deficient in nucleotide excision repair caused by mutations in one of the 7 XP genes. Methods: We diagnosed 181 XP patients using UV-induced DNA repair measurements and/or DNA sequencing from 1982 to 2022 in France. Results: As all XP patients, the French ones are very sensitive to UV exposure but since they are usually very well protected, they develop relatively few skin cancers. A majority of French XP patients originate from North Africa and bear a founder mutation on theXPCgene. The striking discovery is that these patients are at a very high risk to develop aggressive and lethal internal tumors such as hematological malignancies (more than a 100-fold risk compared to the general population for myelodysplasia/leukemia) with a median age of death of 25 years, and brain, gynecological, and thyroid tumors with even lower median ages of death. The high mutation rates found in XP-C internal tumors allow us to think that these XP patients could be successfully treated by immunotherapies. A full analysis of the molecular origins of these DNA repair-deficient tumors is discussed. Several explanations for this high predisposition risk are proposed. Conclusions: As the age of the XP population is increasing due to better photo-protection, the risk of lethal internal tumors is a new Damocles sword that hangs over XP-C patients. This review of the French cohort is of particular importance for alerting physicians and families to the prevention and early detection of aggressive internal tumors in XP patients.