EMMPRIN, a transmembrane glycoprotein known to promote survival, invasion and metastasis of tumor cells through multiple pathways and mechanisms, has been found to be overexpressed in various types of cancer cells. Here we report that loss of the function of p53, a tumor suppressor protein that is mutated in approximately 50% of human cancers, contributes to the upregulation of EMMPRIN protein. We observed an inverse association between the activity of p53 and the level of EMMPRIN protein in several cancer cell lines. We further demonstrated that p53 is able to negatively regulate EMMPRIN protein, but downregulation of EMMPRIN by p53 is independent of repression of the EMMPRIN transcription. Furthermore, downregulation of EMMPRIN by p53 can be rescued by chloroquine, a lysosome inhibitor, but not by MG132, a proteasome inhibitor, suggesting an involvement of the lysosomal pathway in the p53-regulated degradation of EMMPRIN. Downregulation of EMMPRIN by p53 leads to a decrease in the activity of MMP-9 and an inhibition of tumor cell invasion. Our study suggests that the upregulation of EMMPRIN seen in many cancers can be attributed to, at least in part, the dysfunction of p53 and thus provides new evidence for the roles of p53 in tumor development and progression.