We have investigated the presence of c-Myc-like antigens in the enteric nervous system of the guinea-pig, rat, dog, sheep, monkey and human. c-Myc-like immunoreactivity was demonstrated by immunohistochemistry in the enteric nervous system of all animals tested, with one or more monoclonal antibodies raised against peptide sequences found in the human c-Myc protein. While in most cases the labelling was nuclear, cytoplasmic labelling was also observed. In the guinea-pig enteric nervous system, c-Myc-like immunoreactivity detected by two different antibodies remained detectable for up to 4 h in the presence of cycloheximide. The size and density of labelled nuclei in the ileal submucous plexus were consistent with exclusive neuronal labelling by one antibody and neuronal plus glial labelling by the other. Double-labelling with antiserum directed against vasoactive intestinal peptide revealed a subset of c-Myc-immunoreactive neurons that also contain this neuropeptide. Anti-c-Myc antibodies specifically immunoprecipitated proteins from guinea-pig myenteric plexus-longitudinal muscle preparations whose sizes were consistent with previous observations for c-Myc antigens and whose distribution was consistent with synthesis in the myenteric plexus. We conclude that c-Myc proteins are expressed in mammalian enteric neurons and that they have characteristics similar to those of c-Myc proteins in other nonproliferative cells.