Background : Ecabet sodium, a novel non‐systemic anti‐ulcer agent, possesses high affinity to gastric adherent mucus, which plays an important role in the protection of the gastric epithelium against acid and pepsin. Aim : To assess the effect of ecabet on pepsin‐induced degradation of the structure of the mucus gel layer. Methods : Everted sacs of rat stomach were incubated in HCl solution containing pepsin with or without ecabet. Pepsin‐induced release of the cleaved peptides and hexosamine from the sacs was determined. Changes in the molecular size of glycoproteins in the adherent mucus (using gel filtration methods) and in the morphology of the epithelium (using both light and scanning electron microscopy) were also examined. Results : Ecabet reduced the pepsin‐induced release of peptides and hexosamine, depending on its content in the adherent mucus. Pepsin treatment partially lowered the molecular weight of native glycoproteins in the adherent mucus, caused exfoliation of the epithelial cells, and degraded the network‐like ultrastructure of the mucus layer, giving it a lumpy, globular appearance. Ecabet prevented both the pepsin‐induced molecular size shift in mucus glycoproteins, and morphological alteration of the epithelium, including ultrastructural derangement of the mucus gel layer. Conclusion : Ecabet protects the polymeric structure of mucus glycoproteins from proteolytic degradation by pepsin, and thus maintains integrity of the gastric mucus gel layer.