Endotoxic shock is accompanied by significant increases in PAF-acether synthesis, particularly by the lung. The onset of tissue damage and increases in vascular permeability in the gastrointestinal tract correlate temporally with the changes in PAF-acether synthesis and have previously been shown to be inhibited by PAF-acether antagonists. In the present study, the effects of pretreatment with dexamethasone on endotoxin-induced hemoconcentration and hypotension were examined in the rat. Furthermore, the effects of dexamethasone on PAF-acether synthesis and gastrointestinal vascular permeability following administration of endotoxin were also studied. Pretreatment with dexamethasone resulted in a significant attenuation of endotoxin-induced hemoconcentration, hypotension and damage in the duodenum and stomach. Dexamethasone also significantly reduced PAF-acether synthesis by the lung. However, dexamethasone pretreatment had no significant effect on endotoxin-induced increases in PAF-acether release and vascular permeability in the gastrointestinal tissues. The mechanism of the protective actions of dexamethasone may be related to inhibition of the release of PAF-acether from the lung. PAF released from gastrointestinal tissues likely contributes little to the systemic disturbances in endotoxic shock.