LA-N-5 human neuroblastoma cells were found to express high levels of an Mr 53,000 cellular tumor antigen (p53), a protein that has been implicated as playing a fundamental role in the control of cell division and differentiation processes in a variety of tumor systems. When LA-N-5 cells are treated with retinoic acid, they undergo growth and morphological, biochemical, and electrophysiological changes that are characteristic of neuronal maturation and a reduction of the malignant phenotype. We find that these retinoic acid-induced changes are accompanied by a marked decrease in the levels of p53 and p53 mRNA. In our study, p53 levels decreased in concert with both morphological differentiation and with inhibition of cellular proliferation in vitro. These results suggest that p53 levels are intimately related to an undifferentiated phenotype in neuroblastoma cells and support studies which relate p53 levels to the malignant phenotype in other tumor systems.