Lewis antigen expression in upper gastrointestinal epithelium was studied using four monoclonal antibodies to determine the relationship between aberrant differentiation and antigen expression. Specific patterns of type 1 and type 2 Lewis blood group antigen expression were found in the surface and glands of the esophagus, gastric fundus, and duodenum. In biopsy specimens of Barrett's esophagus, gastric fundic-type columnar metaplasia expressed Lewis antigens indistinguishable from those in the normal stomach. In Barrett's junctional and specialized columnar metaplasia, Lewis a antigen was aberrantly expressed on the surface in secretors and in the glands independent of secretor state. Lewis x reactivity was markedly diminished in the glands of Barrett's junctional and specialized columnar epithelium irrespective of secretor state. There was no significant aberrancy observed in the expression of Lewis b and y antigens. The observed aberrant expression of Lewis antigens may be caused by an altered differentiation program in Barrett's metaplastic epithelium and may define a role for these glycoconjugates in the process of metaplasia and carcinogenesis in Barrett's epithelium.