Xeroderma pigmentosum (XP) patients are deficient in nucleotide excision repair (NER) because of mutations in one of the genes coding for NER enzymes. This results predominantly in high frequency of UV-induced skin tumors at an early age; the most severe phenotype is found in patients of complementation group A (XPA). However, in a subset of these XPA patients no skin tumors appear, even at advanced age. Fibroblasts of this subset of patients are not capable of raising UV-induced enhanced reactivation (ER) of viruses and up-regulation of ornithine decarboxylase (ODC). We hypothesized that prevention of ODC induction would protect NER-deficient patients from cancer. To simulate the situation in XPA patients, we used a hairless Xpa knockout mouse model and down-regulated the ODC activity by difluoromethylornithine (DFMO) administered in the drinking water. The DFMO treatment significantly suppressed UV-induced carcinogenesis. In a crossover study, we additionally found that discontinuation of the DFMO treatment resulted in a rapid appearance of skin tumors, up to levels found in mice not treated with DFMO. Late-stage DFMO treatment significantly reduced the number of carcinomas by a factor of 2-3, and it appeared to select for carcinomas with high ODC activity. These results indicate that DFMO suppresses the outgrowth but not the initiation of UV-induced tumors. The DFMO treatment reduced the tumor load but did not offer the Xpa knockout mice full protection against UV carcinogenesis.