Helicobacter pylori is associated with development of gastritis, gastric ulcers, and adenocarcinomas in humans. The Lewis^b (Le^b) blood group antigen mediates H. pylori attachment to human gastric mucosa. Soluble glycoproteins presenting the Le^b antigen or antibodies to the Le^b antigen inhibited bacterial binding. Gastric tissue lacking Le^b expression did not bind H. pylori. Bacteria did not bind to Le^b antigen substituted with a terminal GalNAcα1-3 residue (blood group A determinant), suggesting that the availability of H. pylori receptors might be reduced in individuals of blood group A and B phenotypes, as compared with blood group O individuals.