The effects of platelet aggregation (PA), induced by an intravenous injection of adenosine 5'-diphosphate (ADP), on pulmonary fluid and protein exchange and on arterial blood gases were determined in artificially ventilated sheep prepared with lung lymph fistulas. ADP injection produced small increases (P less than 0.01) in pulmonary lymph flow (Qlym) and transvascular protein clearance (Qlym X lymph-to-plasma protein concentration ratio). These changes were not associated with significant increases in pulmonary arterial and left atrial pressures, pulmonary blood flow, or pulmonary vascular resistance. ADP-induced PA did not increase the pulmonary endothelial permeability to proteins, because an elevation of pulmonary microvascular pressure (Pmv), induced by inflation of a left atrial balloon catheter, produced the same increases in Qlym and protein clearance as in normal sheep after comparable increases in Pmv. The increases in Qlym and protein clearance can be explained by an increase in pulmonary vascular surface area. ADP-induced PA decreased the arterial oxygen tension, which was sustained for the 3 h duration of the study; the arterial carbon dioxide tension did not change and the arterial pH decreased (P less than 0.05) after PA. Chronic depletion of platelets with antiplatelet serum prevented the increases in Qlym and protein clearance and the arterial hypoxemia, indicating that these changes were the direct result of PA. Thus ADP-induced PA in sheep increased pulmonary fluid filtration and protein clearance by an increase in the vascular surface area. Also PA produced a rapid and prolonged arterial hypoxemia, which may result from the release of vasoactive and bronchoactive factors causing a maldistribution of ventilation and perfusion.