Immunohistochemistry was performed on biopsies of columnar mucosa from 11 patients with Barrett's esophagus and 11 patients with columnar mucosa in the cranial esophagus, the "inlet patch." Both epithelia contained endocrine cells, immunoreactive to antisera against serotonin, glucagon, somatostatin, and pancreatic polypeptide; the specialized mucosa of Barrett's esophagus contained, in addition, neurotensin-immunoreactive cells, and in the mucosa of an inlet patch we found a gastrin cell. These findings are not compatible with some of the current theories on the origin of these epithelia. The mucosa of the inlet patch has been considered to consist of heterotopic gastric mucosa. The mucosa of the adult human stomach, however, does not contain glucagon cells. These cells are only present in the early embryonic stomach, and they disappear during embryonogenesis. According to our findings, the mucosa of the inlet patch therefore represents embryonic gastric mucosa. The specialized columnar epithelium of Barrett's esophagus has been considered to have evolved from gastric mucous neck cells. However, although glucagon cells are a feature of the embryonic stomach, neurotensin-immunoreactive cells have not been found in the gastric mucosa. Our study suggests that the specialized columnar epithelium of Barrett's esophagus originates from a very immature multipotent gastrointestinal stem cell.