The mechanism(s) of salicylate-induced dam-age of the gastric mucosa is complex. The presence of acid in the lumen is essential for the occurrence of such injury. Although the absorption of salicylate is greater in the presence of acid, salicylate can selectively increase cation permeability both in the absence and presence of acid. Recent studies suggest that this permits increased diffusion of luminal acid into the tissue, which leads to major permeability changes of the mucosa. Salicylate also affects metabolic processes of the gastric mucosa, which appear to be independent of the increased diffusion of acid into the tissue also caused by salicylate. The release of histamine, which has been shown to occur in vivo as a result of mucosal damage, does not appear to intensify existing mucosal injury in an isolated system.