Telomere dysfunction and shortening induce chromosomal instability and tumorigenesis. In this study, we analyze the adrenocortical dysplasia (acd) mouse, harboring a mutation in Tpp1/Acd. Additional loss of p53 dramatically rescues the acd phenotype in an organ-specific manner, including skin hyperpigmentation and adrenal morphology, but not germ cell atrophy. Survival to weaning age is significantly increased in Acdacd/acd p53−/− mice. On the contrary, p53−/− and p53+/− mice with the Acdacd/acd genotype show a decreased tumor-free survival, compared with Acd+/+ mice. Tumors from Acdacd/acd p53+/− mice show a striking switch from the classic spectrum of p53−/− mice toward carcinomas. The acd mouse model provides further support for an in vivo role of telomere deprotection in tumorigenesis.