The tumor suppressor p53 induces potent anti-proliferative responses in stressed cells; in unstressed cells this ability of p53 is restrained by Hdm2. Expression of Hdm2 is also induced by p53, thereby establishing feedback inhibition. Regulation of the p53-Hdm2 interaction and the feedback inhibition of p53 are not well understood. Here, we show that the p53-Hdm2 interaction in unstressed cells is promoted by Siva1, which, like Hdm2, is the product of a p53 target gene. Siva1 binds to both p53 and Hdm2 through distinct regions and enhances Hdm2-mediated p53 ubiquitination and degradation. Siva1 strongly inhibits p53-mediated gene expression and apoptosis. In xenograft mouse models, downregulation of Siva1 markedly inhibits tumor formation because of the activation of p53. On DNA damage, the interactions of Siva1 with both p53 and Hdm2 are diminished. The function of Siva1 seems to be related to its ability to form a homo-oligomer as the oligomerization defective splicing variant Siva2 fails to de-stabilize p53. These results identify Siva1 as an important adaptor promoting p53 degradation through Hdm2. Siva1 may be part of the negative feedback loop that inhibits p53 activity at the end of a non-lethal stress response.