The common neurotrophin receptor p75(NTR) has been shown to initiate intracellular signaling that leads either to cell survival or to apoptosis depending on the cell type examined; however, the mechanism by which p75(NTR) initiates its intracellular transduction remains unclear. We show here that the tumor necrosis factor receptor-associated death domain protein (TRADD) interacts with p75(NTR) upon nerve growth factor (NGF) stimulation. TRADD could be immunodetected after p75(NTR) immunoprecipitation from MCF-7 breast cancer cells stimulated by nerve growth factor. In addition, confocal microscopy indicated that NGF stimulation induced the plasma membrane localization of TRADD. Using a dominant negative form of TRADD, we also show that interactions between p75(NTR) and TRADD are dependent on the death domain of TRADD, thus demonstrating its requirement for binding. Furthermore, the p75(NTR)-mediated activation of NF-kappaB was inhibited by transfection with a dominant negative TRADD, resulting in an inhibition of NGF antiapoptotic activity. These results thus demonstrate that TRADD is involved in the p75(NTR)-mediated antiapoptotic activity of NGF in breast cancer cells.