The neurotrophin nerve growth factor (NGF) supports neuronal survival by activating the transcription factor nuclear factor-kappaB (NF-kappaB). We report here, for the first time, the identification of p75-associated kinase that mediates NGF-driven NF-kappaB activation. Using co-immunoprecipitation, we demonstrate an NGF-dependent association of interleukin 1 receptor-associated kinase (IRAK) with the p75 neurotrophin receptor in PC12 cells. Our results reveal that IRAK is recruited to the p75-NGF receptor leading to formation of a complex between IRAK, atypical protein kinase C interacting protein, p62, and TRAF6. Activation of NF-kappaB occurs predominantly through the p75 receptor, and TrkA activity suppresses NF-kappaB activation and retards IkappaBbeta degradation. In addition, we observe a requirement for the kinase activity of IRAK in mediating NGF-induced NF-kappaB activation, recruitment of the adapter protein p62 to the p75 receptor, and cell survival. Moreover, p75-IRAK-mediated kappaB activation and the recruitment of IKKbeta, but not IKKalpha, to the receptor require p62. Altogether, our data provide novel information regarding the proximal components involved in p75 receptor signaling and underscore the importance of the atypical PKC interacting protein p62 in this process.