Nerve growth factor binds independently to two transmembrane receptors, the p75 neurotrophin receptor and the p140trk (trkA) tyrosine kinase receptor, which are both co-expressed in the majority of neuronal cells that respond to NGF. Previous findings have suggested that appropriate co-expression of the two receptors gives rise to high affinity NGF binding sites and increased neurotrophin responsiveness; however, evidence demonstrating a direct interaction between the two receptors in cell lines has been lacking. Here we have utilized affinity crosslinking agents with 125I-NGF to detect an association of trkA and p75 receptors in embryonic spinal cord and brain tissues enriched in the two receptors. Although multimeric complexes of trkA and p75 were not detected by affinity crosslinking, immunoprecipitation of cross-linked NGF-receptor complexes with trk-specific antibodies resulted in selective immunoprecipitation of crosslinked p75. Our results indicate that the trkA and p75 receptors can potentially interact, and that such an association may be responsible for the generation of high affinity NGF binding sites.