The effect of prolonged administration of an antiulcer drug, sofalcone, on the physicochemical properties of gastric mucus was investigated. The experiments were conducted with two groups of rats in which one group received a dose of 100 mg/kg of sofalcone twice daily for three consecutive days, and the control group received daily doses of vehicle. The rats were killed 16 h after the last dose, their stomachs dissected, and the mucosa subjected to physicochemical measurements. The results revealed that sofalcone evoked a 23% increase in mucus gel thickness, and its content of sulfo- and sialomucins increased by 54 and 25%, respectively. These changes in mucus with sofalcone were accompanied by a 16% increase in H+ retardation capacity, twofold increase in viscosity, and a 39% increase in the gel hydrophobicity. The mucus elaborated in the presence of sofalcone exhibited a 10% lower content of protein, 30% higher content of carbohydrate, and 18% higher content of total lipids, which were particularly enriched (20%) in phospholipids and contained 67% more covalently bound fatty acids. Furthermore, the high molecular weight mucus glycoprotein form accounted for about 30% of gel mucin in the control group, whereas its content in mucus gel of animals receiving sofalcone reached 50%. The results indicate that sofalcone enhances the protective qualities of the mucus component of the gastric mucosal barrier and hence strengthens the gastric mucosal integrity.