Enkephalin-like immunoreactivity was demonstrated in nerves in the esophagus of guinea-pig, opossum, cat, pig, monkey, and humans. Immunoreactive nerves were found in the external muscle layer and in the muscularis mucosae. In the myenteric plexus immunoreactive nerve fibers were numerous; immunoreactive nerve cell bodies were observed only occassionally. Enkephalin nerves appeared early (the 7th wk of gestation) in porcine fetuses; at this stage the nerves were confined to the myenteric plexus. Motor effects of enkephalin were studied on segments from circular smooth muscle of cat esophagus. Enkephalin inhibited electrically induced contractions in a dose-dependent manner. This effect was blocked by naloxone. The results suggest that enkephalin nerves may be involved in the regulation of esophageal motility. Like enkephalin, bretylium (a blocker of adrenergic transmission) and phentolamine (on alpha-adrenergic blocker) prevented the contractile response to electrical stimulation. With smooth muscle strips from reserpinized cats the response to electrical field stimulation was abolished, but not the response to norepinephrine. Taken together, the results suggest that neuronal enkephalin in the esophagus functions as a modulator of adrenergic transmission.