In breast cancer cells, the neurotrophin receptor p75NTR acts as a prosurvival factor able to stimulate resistance to apoptosis, but its mechanism of action remains incompletely defined. In this study, we investigated the global proteome modification induced by p75 NTR overexpression in breast cancer cells treated by the pro-apoptotic agent tumor necrosis factor (TNF)-related-apoptosis-inducing-ligand (TRAIL). p75 NTR was stably overexpressed in the MCF-7 breast cancer cells and the impact of a treatment by TRAIL was investigated in wild type vs. p75 NTR overexpressing cells. Proteins were separated in two-dimensional electrophoresis, and regulated spots were detected by computer assisted analysis before identification by MALDI-TOF/TOF mass spectrometry. In the absence of TRAIL treatment, p75 NTR did not induce any change in the proteome of breast cancer cells. In contrast, after treatment with TRAIL, fragments of cytokeratin-8, -18 and -19, as well as full length cytokeratin-18, were up-regulated by p75 NTR overexpression. Of note, spectrin alpha-chain and the ribosomal protein RPLP0 were induced by TRAIL, independently of p75 NTR level. Interestingly, the well known stress-induced protein HSP-27 was less abundant when p75 NTR was overexpressed, indicating that p75 NTR overexpression reduced TRAIL induced cell stress. These data indicate that overexpression of p75 NTR induces proteome modifications in breast cancer cells and provide information on how this receptor contributes in tumor cell resistance to apoptosis.