Fasted, anesthetized female rats were used to test the effects of sucralfate (Sc) on the response of the gastric mucosa to ethanol (EtOH) in NaCl or taurocholic acid (TcA) in HCl. The trachea was cannulated and the esophagus and pylorus were ligated. Tubes placed into the stomach permitted instillation of test solutions and determinations of transmucosal potential difference (PD). All periods were 15 min. Each test began with a baseline 150 mM HCl period followed by two treatment periods; in the first, 5600 mg Sc in NaCl or NaCl alone was placed in the stomach; in the second, neutral EtOH or acidified TcA solution was added. In the final two posttreatment test periods, the pH of the gastric contents of the animals treated with Sc was higher, the disappearance of H+ was less, and the index of mucosal damage was reduced. The results demonstrate that Sc has a protective effect on the gastric mucosa of rats. Pretreatment with Sc also reduced the net Cl-loss from the contents and produced an unexplained significant reduction in PD. Sc formed a white coating over the glandular mucosa. This coating may a play a role in its protective action.