Hox genes encode transcription factors of crucial importance in the pattern formation of a large spectrum of species. Several studies have now proposed a role for these developmental genes in cancer biology. It has been suggested that HOXA5 possesses growth-suppressive properties through activation of p53 expression in human breast tissue. To assess the genetic cooperation that may exist between Hoxa5 and p53 in tumorigenesis, we generated Hoxa5/p53 compound mutant mice. The presence of Hoxa5 null alleles increased the susceptibility of p53(-/-) mice to develop tumors with a high prevalence for thymic lymphoma, suggesting that the loss of function of the two genes collaborate in tumor formation. To extend our analysis to mammary tumorigenesis, we performed Hoxa5/p53 whole mammary gland transplantations into wild-type hosts. In the p53(-/-) background, the presence of one Hoxa5 mutant allele had no impact on mammary tumor formation. In contrast, the complete loss of Hoxa5 function influenced the tumorigenic outcome of p53(+/-) mammary glands. However, the collaborative nature of this interaction did not depend on the transcriptional regulation of p53 by Hoxa5. Altogether, our data establish that Hoxa5 and p53 cooperate in mammary tumorigenesis in vivo.