In addition to the Trk tyrosine kinase receptors, neurotrophins also bind to a second receptor, p75, a member of the tumor necrosis factor receptor superfamily. Several signaling pathways have been implicated for p75 in the absence of Trk receptors, including induction of NF-kappaB and c-Jun kinase activities and increased production of ceramide. However, to date, the mechanisms by which the p75 receptor initiates intracellular signal transduction have not been defined. Here we report a specific interaction between p75 and TRAF6 (tumor necrosis factor receptor-associated factor-6) after transient transfection in HEK293T cells. The interaction was ligand-dependent and maximal at 100 ng/ml of nerve growth factor (NGF). Other neurotrophins also promoted the association of TRAF6 with p75 but to a lesser extent. The binding of TRAF6 was localized to the juxtamembrane region of p75 by co-immunoprecipitation and Western blotting. To assess the functional significance of this interaction, we have tested responses in cultured Schwann cells that express p75 and TRAF6. An NGF-mediated increase in the nuclear localization of the p65 subunit of NF-kappaB could be blocked by the introduction of a dominant negative form of TRAF6 in Schwann cells. These results indicate that TRAF6 can potentially function as a signal transducer for NGF actions through the p75 receptor.