Human gastric mucus has been obtained from mucosal scrapings of gastric resection specimens. The glycoprotein was isolated from the mucus gel--undegraded and free of noncovalently bound protein--by equilibrium centrifugation in a CsCl density gradient. Ultracentrifugation studies showed this glycoprotein was a single component of molecular weight of 2 X 10(6). Analysis by gel filtration showed the undegraded glycoprotein was a polymer that was split into glycoprotein subunits, of about 5 X 10(5) mol wt, by pepsin and other proteolytic enzymes. Reduction with mercaptoethanol, but not with 2 M NaCl, also split the glycoprotein into subunits, which indicated that these subunits are joined together by disulphide bridges to form the undegraded glycoprotein. This structure is very similar to that described for the previously characterized pig gastric mucus glycoprotein, and it shows that results obtained using pig gastric mucus as a model are directly applicable to human gastric mucus. It also follows that pepsin in humans, by destroying this polymeric structure of the constituent glycoproteins, solubilizes the surface mucus gel, and liberates the degraded glycoprotein subunits into the gastric lumen. The relevance of this to changes in the thickness of the surface mucus gel in vivo and possible effects on mucosal protection in pathologic conditions is discussed.