The p75 neurotrophin receptor (p75NTR), a common receptor for members of the neurotrophins (NT) family, was previously identified as a molecular determinant of brain metastasis. We have also reported that NT treatment of murine and human brain-metastatic melanoma cells affects their invasive capacities and increases the production of heparanase, an important and unique extracellular matrix (ECM) degradative enzyme. Neurotrophism can be a survival-support mechanism for brain-metastatic cells and a survival assay was devised to mimic the growth limiting conditions of rapidly expanding metastatic tumors prior to neoangiogenesis. We report that p75NTR promoted the survival of brain-metastatic melanoma cells but not melanocytes in stress cultures conditions. Secondly, melanoma cells fluorescently sorted for high p75NTR expression (p75NTR-H cells) had an up to a 15-fold greater survival than those sorted for low p75NTR expression (p75NTR-L cells). Thirdly, cells overexpressing p75NTR associated with the growth fraction and provided these cells with an inherent growth advantage. Finally, we observed an increased survival of sorted p75NTR-L cells, dependent upon treatment of NT members whose functional receptors are present on these cells. Together, these results delineate that p75NTR-mediated trophic support profoundly affects competitive melanoma-cell survival when the tumor cell microenvironment becomes growth limiting. © 2003 Wiley-Liss, Inc.