The potential role of platelet-activating factor (PAF) as a mediator of gastrointestinal ulceration associated with septic shock was examined in the rat. The damaging effects of both PAF and Escherichia coli endotoxin in the stomach and small intestine were compared, as were their effects on plasma leakage into the lumen of the gastrointestinal tract. Intravenous administration of either endotoxin or PAF produced extensive necrosis and vascular congestion in the stomach and small intestine, but not the distal colon. With either agent, the duodenum and jejunum were the tissues most susceptible to damage and in which the greatest plasma leakage was observed. The prolonged hypotension and gastrointestinal damage induced by PAF or endotoxin were significantly inhibited by three structurally dissimilar PAF antagonists (CV-3988, BN-52021, and Ro-193704). CV-3988 (10 mg/kg) significantly (p less than 0.05) reduced both endotoxin- and PAF-induced plasma leakage in the stomach and small intestine. Of the three antagonists, only CV-3988 significantly reduced ethanol-induced gastric mucosal damage, perhaps reflecting actions of this compound unrelated to antagonism of PAF receptors. These studies support the hypothesis that PAF is an important mediator of the hypotension and plasma leakage observed during endotoxic shock and its endogenous release may contribute to the gastrointestinal ulceration associated with this syndrome. Thus, PAF receptor antagonists may be useful for prevention of such ulceration.