Neuroblastoma, the most common extracranial tumor of childhood, is derived from neural crest progenitor cells that fail to differentiate along their predefined route to sympathetic neurons or sympatho-adrenergic adrenal cells. Although expression of the high-affinity neurotrophin receptors, TrkA and TrkB, is of major importance in neuroblastoma, the significance of the expression of the low-affinity neurotrophin receptor, p75, is unclear. Here, we analyzed immunohistochemically expression of p75 on a tissue microarray of 93 primary neuroblastic tumors and assessed the functional consequences of p75 expression in neuroblastoma cell lines. We found the p75 receptor protein to be expressed in neuroblastic cells of ganglioneuromas/ganglioneuroblastomas as well as differentiating neuroblastomas, but not in poorly differentiated neuroblastomas. In an unrelated cohort of 110 neuroblastic tumors, p75 mRNA expression levels correlated with differentiation, and patients with tumors that expressed p75 at high levels had an increased event-free and overall survival. In addition, we did not detect p75 expression in 8 established neuroblastoma cell lines examined with FACS analysis. These cell lines exhibited an undifferentiated morphology, and were all derived from aggressive, high-stage neuroblastomas. Ectopic p75 expression in the SH-SY5Y neuroblastoma cell line significantly reduced proliferation, increased the fraction of apoptotic cells in vitro and resulted in a loss of tumorigenicity in nude mice. Taken together, our data suggest that expression of the p75 low-affinity neurotrophin receptor is correlated with a reduced level of tumorigenicity, and that induction of p75 expression may be an option to revert features of an aggressive tumor phenotype. © 2008 Wiley-Liss, Inc.