Zinc and vitamin A are known to interact, and deficiencies have been associated with carcinogenesis in experimental animals and humans. Since we previously have demonstrated decreased plasma zinc and vitamin A levels in patients with esophageal cancer, we wished to examine endoscopically obtained epithelial tissue for vitamin A and zinc content. This was not feasible for vitamin A, but using newly developed techniques for zinc analysis of small tissue samples, we measured esophageal epithelial zinc as well as plasma zinc and plasma vitamin A in 21 patients with esophageal cancer, 17 patients with esophagitis, and 12 normals. Mean plasma zinc in the esophageal cancer group (56 +/−3 micrograms/dl) (mean +/−SEM) was significantly less than in the esophagitis group (72 +/−5 micrograms/dl) and the normals (78 +/−5 micrograms/dl). Mean plasma vitamin A in the esophageal cancer group (32 +/−3 micrograms/dl) was significantly less than the esophagitis group (57 +/−4 micrograms/dl) or the normals (58 +/−5 micrograms/dl). There was no significant difference in tissue zinc content (measured as micrograms zinc/g wet weight of tissue, mean +/−SEM) among cancerous tissue (57 +/−5 micrograms/g) and adjacent normal tissue (61 +/−4 micrograms/g), esophagitis tissue (66 +/−6 micrograms/g) and adjacent normal tissue (61 +/−6 micrograms/g), or normal esophageal tissue (59 +/−6 micrograms/g). We conclude that deficiencies of zinc or vitamin A may be cofactors in the induction of human esophageal cancer, but a mechanism cannot be accounted for by differences in epithelial zinc content.