Neurotrophins mediate their effects by binding to members of the Trk family of receptor tyrosine kinases and the neurotrophin receptor p75 [1]. Whereas Trks are essential for the trophic effects of neurotrophins [1], p75 has distinct functions in different cells. For example, it enhances the survival response of certain neurons to nerve growth factor (NGF) [2], but mediates a cytotoxic response to NGF in certain other cell types and neurons [3] [4] [5] [6]. We investigated whether the p75-mediated responses to NGF can be modulated through the activation of different signalling pathways in the same neurons. Neurons of the embryonic trigeminal mesencephalic nucleus (TMN) are supported in culture by brain-derived neurotrophic factor (BDNF) and an unrelated neurotrophic factor, ciliary neurotrophic factor (CNTF), but not by NGF [7] [8] [9]. We found that NGF killed TMN neurons that were grown in the presence of CNTF; this effect of NGF was inhibited by anti-p75 antibodies and therefore occurred via a p75-dependent mechanism. NGF did not affect the survival of neurons grown in the presence of BDNF, and very low concentrations of BDNF inhibited NGF cytotoxicity. These results indicate that the activation of different signalling pathways in TMN neurons influences their susceptibility to p75-mediated NGF cytotoxicity.