The role of the gastric nonwettable hydrophobic layer (surfactant) was investigated in the mucosal protection against the damage induced by ethanol in the rat. Although aluminium hydroxide inhibited the development of ethanol-produced gastric hemorrhagic lesions, it did not increase the mucosal phospholipid content. Ambroxol, a known stimulant of pulmonary surfactant production, protected the gastric mucosa against ethanol by increasing the phospholipid content. Surface-active compounds such as dimethyl polysiloxane also inhibited the development of gastric injuries caused by ethanol in a dose-dependent manner. The essential phospholipid-containing drug (Essentiale) also showed a strong and dose-dependent cytoprotective effect. Among the possible constituents of the gastric surfactant, sphingomyelin was totally ineffective. Phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol were able to reduce the extent of mucosal damage in a dose-dependent manner. Gastric mucosal injuries were significantly aggravated by pretreatment with phospholipase C. In conclusion, these results suggest that either the maintenance or the strengthening or even the replacement of the gastric nonwettable hydrophobic lining between the damaging agent and the gastric mucosa may contribute to the cytoprotective mechanism of certain compounds.