The purpose of this study was to determine the effect of lysophosphatidylcholine on the guinea pig stomach after dosing the animal with 20% ethanol by orogastric intubation. We studied four groups of animals; one control group received saline orogastrically followed by buffer and one test group received saline followed by buffer plus 1 mM lysophosphatidylcholine. Two other groups were challenged with 20% ethanol (5 ml) orogastrically followed by buffer or buffer plus 1 mM lysophosphatidylcholine. Compared to other groups, the stomachs of animals given ethanol followed by lysophosphatidylcholine displayed statistically significant increases in the number of gross hemorrhagic lesions, in back-diffusion of hydrogen ion, in net secretion of sodium ion, and in morphologic damage. Transmucosal potential differences in this group were also decreased. We conclude that 90 min after dosing with ethanol, the guinea pig stomach is more susceptible to damage by lysophosphatidylcholine. Our data further suggest that these agents cause mucosal damage by different mechanisms and that the combination acts synergistically.