The p53 protein is a pivotal tumour suppressor that is frequently mutated in human cancers. Precisely how p53 prevents tumours is still unclear, and the recent discovery of twelve p53 isoforms only adds to this complexity. To determine the functions of the human Δ133p53 isoform we generated a mouse equivalent, Δ122p53. The Δ122p53 mice display a different and more aggressive tumour spectrum compared to p53 null mice. Additionally these mice also suffer from a pro-inflammatory phenotype. Taken together, these observations imply that Δ122p53 has additional properties other than just inhibiting full length p53. Indeed, in vitro experiments show that expression of either Δ122p53 or Δ133p53 in p53 null cell lines results in an increase in cellular proliferation. Here we report that Δ133p53 binds to and inhibits the p53 family members p63 and p73, preventing them from mediating growth inhibition and regulating transcription of their target genes, including the repression of pro-inflammatory signals. These results give us insights in the role of Δ133p53 and the roles of the p53 family members in repressing tumours and possibly also inflammation.