Studies using a gastric chamber model demonstrated that sucralfate protected the rat gastric mucosa against hemorrhagic erosions induced by 40 percent ethanol and by acidified 80 mM sodium taurocholate. Protection required continuous contact of sucralfate with the gastric mucosa but it occurred without the production, by sucralfate alone, of significant damage to the luminal epithelium. Ultrastructural examination indicated that sucralfate stimulated mucus secretion by surface epithelial cells. Furthermore, sucralfate was "cytoprotective" in that, in addition to its anti-ulcer effects, it significantly reduced the damaging effects of luminal ethanol on the surface epithelium. Luminal stasis also significantly reduced the extent of hemorrhagic erosions produced by both ethanol and sodium taurocholate, but the most effective reduction in erosions occurred when sucralfate and luminal stasis were combined. Pretreatment with indomethacin abolished the protection provided by luminal stasis, but this protection was restored by sucralfate. Thus, these studies suggest that protection of the gastric mucosa by sucralfate results in part from effects on the unstirred layer. Sucralfate or its products also interact with the epithelial cells and stimulate mucus release and synthesis or release of inflammatory mediators.