It has been shown that intragastric treatment of rats with a suspension of dipalmitoylphosphatidylcholine and tripalmitin at a 1:4 ratio (5 mg lipid/mL per rat) provided rats with highly efficaceous and consistent protection against a variety of ulcerogenic agents and conditions. The gastric protective activity of this mixture was of long duration (t 1/2 approximately 9 hours. In an attempt to understand the mechanism of protection, it was determined that the ulcerogen-induced reduction in gastric surface hydrophobicity was reversed in rats pretreated with the mixture. However, the lipid mixture did not affect the gastric emptying rate and maintained its cytoprotective activity in indomethacin-treated rats. These results indicate that the mixture's protective effect was not mediated by alterations in either gastrointestinal motility or the gastric accumulation of lipids or "cytoprotective" metabolites (prostaglandins). The mixture also appreciably reduced gastric lesion score in response to acid if one or both the lipids was substituted for a metabolically inert ether analogue, suggesting that lipid metabolism makes a negligible contribution to the protective response. Electron microscopic observation indicated that the predominent structure in the mixture is a microemulsion in which a dipalmitoylphosphatidylcholine monolayer encapsulates a tripalmitin core. Last, the improved gastric protective activity of the mixture in comparison to dipalmitoylphosphatidylcholine liposomes is discussed regarding marked differences in the physical structure of the two suspensions and the rate at which lipids in these states adsorb to a surface to enhance its hydrophobic properties.