OBJECTIVE To evaluate the contribution of hematocrit and RBC deformability to pulmonary vascular pressures of racehorses. METHODS Pony lungs were isolated and right and left lungs were perfused separately with blood. The effects of changing hematocrit and of pentoxifylline treatment were evaluated. METHODS 11 healthy mixed-breed ponies. METHODS Ponies were anesthesized, blood was collected, and lungs were removed and perfused with blood at constant flow rate. RESULTS Increasing the hematocrit from 35% to 65% resulted in increases in pulmonary arterial pressure (53%, 45%), capillary shear stress (45%, 32%), and total vascular resistance (92%, 143%) at low (352 +/- 33 ml/min) and high (1,442 +/- 48 ml/min) flow rates, respectively. Pulmonary artery pressures were lower (10%, 11%) when lungs were perfused with blood from pentoxifylline-treated ponies, compared with blood from control ponies with low hematocrit (PCV, 30%) and low-flow rate and with high hematocrit (PCV, 45%) and high flow rate, respectively. Decreases in capillary shear stress and total vascular resistance were also observed for pentoxifylline-treated blood. CONCLUSIONS Increases in hematocrit equivalent to those occurring during competitive racing activity contribute substantially to pulmonary vascular pressures in horse lungs. Administration of pentoxifylline to ponies reduced RBC deformability and attenuated increases in pulmonary vascular pressures. CONCLUSIONS Treatment of racehorses with pentoxifylline may reduce exercise-associated increases in pulmonary vacular pressure, thereby attenuating exercise-induced pulmonary hemorrhage.