The effect of platelet-activating factor (PAF) on the changes in the lung following inhalation of endotoxin has been studied by using the PAF receptor antagonist, RP 48740 in animal model systems. It was found to blunt (but not abolish) the 24 hr neutrophil and macrophage free lung cell responses in guinea pig bronchoalveolar lavages, but had no effect on the platelet infiltrations. Lungs from hamsters treated with LPS aerosols alone were easy to distinguish from those subjected to saline aerosols by evidence seen at the light and electron microscopic levels. LPS-exposed animals pretreated with the RP 48740 were virtually indistinguishable from saline controls. Finally, pretreatment with RP 48740 significantly inhibited LPS-induced increases in pulmonary capillary permeability. These results suggest that the pulmonary capillary platelet accumulation seen after exposure to endotoxin could be mediated by the production of PAF and lead to many of the subsequent inflammatory effects known to be induced by endotoxin inhalation.