We studied the expression of pro-apoptotic neurotrophin receptor p75 (p75NTR) in human and murine retinoblastoma, compared to normal retina, and examined changes in p75NTR expression with the onset of apoptosis in the course of murine retinoblastoma progression, using immunohistochemistry and quantitative real-time RT-PCR. The murine retinoblastoma is induced by retinal specific expression of SV40 T-antigen (TAg), which blocks the function of the retinoblastoma protein (pRB) and related proteins, and is a well-studied model that closely simulates human retinoblastoma. The majority of human retinoblastoma either lacked or expressed decreased levels of p75NTR mRNA, compared to human retina. Moreover, p75NTR protein was not detected in any tumor studied, unlike normal retina. Like human retinoblastoma, advanced murine retinoblastoma did not express p75NTR. However, before tumors emerged, small clusters of TAg-positive cells coexpressed p75NTR and activated caspase-3, a marker of apoptosis. Furthermore, in three rare human eyes containing retinoblastoma adjacent to regions resembling the benign retinal tumor retinoma, both normal retina and retinoma-like tissue expressed p75NTR protein, while the retinoblastoma did not. We suggest that p75NTR loss accompanies progression from retinoma to retinoblastoma. © 2006 Wiley-Liss, Inc.