The cytoplasmic region of the common neurotrophin receptor (p75NGFR) (rat, human, chick) contains a putative membrane-associating domain implicated in intracellular signalling. A peptide (R3) identical to this domain (p75NGFR 367–379) and various analogues of this peptide displayed circular dichroism spectra in aqueous and non-polar environments identical to the amphiphilic tetradecapeptide mastoparan (MP) and were internalized by PC12 rat pheochromocytoma cells. The R3 peptide enhanced neurite growth in PC12 cells, embryo chick primary sensory neurons and fetal rat primary sensory neurons in vitro in the presence of sub-saturating concentrations of NGF. Peptide analogues of R3 not faithful to the distance and angular relationships of ionic groups and the putative amphiphilic structure of p75NGFR 367–379 displayed reduced potency to enhance NGF-mediated neurite growth. Exposure of NGF and the R3 peptide to a cell line displaying predominantly p75NGFR (PC12nnr5), had no influence on neurite growth. The R3 peptide had no effects on cell survival, cell binding or uptake of [125I]NGF, affinity cross-linking of [125I]NGF to p75NGFR or trkA monomers and homodimers, or NGF-mediated trkA monomer tyrosine phosphorylation. The studies implicate a role for a highly conserved motif of p75NGFR in the downstream modulation of NGF-mediated neurite growth.