CD43 (leukosialin, sialophorin), a cell surface protein on most hematopoietic cells, is an important regulator of immune cell function and is involved in regulation of cell adhesion and proliferation. Aberrant expression of CD43 is a common event observed in human tumors of non-hematopoietic origin suggesting a role in tumor development. We have previously shown that overexpression of CD43 causes activation of the ARF-p53 tumor-suppressor pathway and results in cell death. In a non-functional ARF-p53 background, the cells overexpressing CD43 display an increased cell growth rate due to higher survival. Here we show that p53 specifically downregulates the expression of CD43 at the protein and mRNA level. Transactivating properties of p53 are necessary to affect the expression of exogenous CD43. The downregulation of CD43 mRNA is caused by p53-dependent transrepression, at least in part, via a histone deacetylation mechanism. These studies establish that under certain conditions there exists a negative feedback loop between p53 and CD43: CD43-dependent signaling activates p53, which in turn downregulates the expression of CD43.