p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, we studied the influence of mutant p53 (mut-p53) on somatic cell reprogramming. Our data indicate a novel gain of function (GOF) property for mut-p53, which markedly enhanced the efficiency of the reprogramming process compared with p53 deficiency. Importantly, this novel activity of mut-p53 induced alterations in the characteristics of the reprogrammed cells. Although p53 knockout (KO) cells reprogrammed with only Oct4 and Sox2 maintained their pluripotent capacity in vivo, reprogrammed cells expressing mutant p53 lost this capability and gave rise to malignant tumors. This novel GOF of mut-p53 is not attributed to its effect on proliferation, as both p53 KO and mut-p53 cells displayed similar proliferation rates. In addition, we demonstrate an oncogenic activity of Klf4, as its overexpression in either p53 KO or mut-p53 cells induced aggressive tumors. Overall, our data show that reprogrammed cells with the capacity to differentiate into the three germ layers in vitro can form malignant tumors, suggesting that in genetically unstable cells, such as those in which p53 is mutated, reprogramming may result in the generation of cells with malignant tumor-forming potential.