Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) selectively bind to distinct members of the Trk family of tyrosine kinase receptors, but all three bind with similar affinities to the neurotrophin receptor p75 (p75^NTR). The biological significance of neurotrophin binding to p75^NTR in cells that also express Trk receptors has been difficult to ascertain. In the absence of TrkA, NGF binding to p75^NTR activated the transcription factor nuclear factor kappa B (NF-κB) in rat Schwann cells. This activation was not observed in Schwann cells isolated from mice that lacked p75^NTR. The effect was selective for NGF; NF-κB was not activated by BDNF or NT-3.