The role of platelet-activating factor (PAF) in inhalation injury was studied in sheep, using CV-3988, a PAF antagonist. Following smoke exposure, 15 sheep were divided into three groups of five. Group I animals were untreated; group II animals were treated with CV-3988 before and after exposure; group III animals were treated only after exposure. In group I, platelet and WBC counts were markedly changed within 6 hours (p less than 0.05); in the treated groups, alteration of cell counts was not obvious. Blood malondialdehyde (MDA) levels were increased significantly only in group I. Blood PGE2 and TXB2 levels did not differ among the groups. Mean tissue MDA and mean bronchoalveolar lavage fluid (BALF) MDA concentrations were significantly increased in group I (p less than 0.01); mean BALF TXB2 levels were significantly decreased in group I (p less than 0.01). These data suggest that PAF affects inhalation injury through modulation of lipid oxygenation and that PAF antagonists may offer therapeutic benefit in the management of this injury.