Localization of calcitonin gene-related peptide in human esophageal Langerhans cells. Previously undescribed calcitonin gene-related peptide-immunoreactive intraepithelial cells were seen in specimens of esophageal mucosa obtained by biopsy or surgical resection from 14 individuals. These calcitonin gene-related peptide-immunoreactive cells were sparsely seen in normal mucosa but increased markedly in esophagitis. They were inaccessible to routine histological stains, but osmication showed them as dendritic forms resembling Langerhans cells of the skin. Their cytological identity was determined with immunocytochemical tests for human antigenic markers such as Ia, HLA-DR, and OKT6 for Langerhans cells, Leu-M5 and Leu-M3 for intraepithelial macrophages, CD3 and TCR-1 for T-lymphocytes, Leu-14 for B-lymphocytes, S-100 for Merkel cells, and chromogranin for amine precursor uptake and decarboxylation cells. Double localization showed that calcitonin gene-related peptide immunoreactivity colocalized with Ia, HLA-DR, and OKT6 but not with the other markers. These studies show that intraepithelial Langerhans cells in the esophageal mucosa contain calcitonin gene-related peptide, which may serve as an immunomodulator. 