Protamine reversal of heparin is often associated with severe hemodynamic side-effects, including pulmonary hypertension in cardiovascular surgery. However, the precise mechanism of this transient pulmonary hypertension is not clear. Recently, it was reported that pulmonary intravascular macrophages (PIM) react avidly with and phagocytize various foreign particles (liposome, latex, red cells). Sheep, goat and pig have a large population of PIM, but rabbit, rat and human have few. To investigate whether the pulmonary reaction after protamine reversal is related to PIM, we compared the pulmonary reaction after protamine reversal between goats and rabbits. We also studied it in patients for cardiac surgery. Protamine sulphate (2 mg.kg-1) was injected in 2.5 min into femoral artery at five min after heparin sodium (200 IU.kg-1) injection in goats and rabbits. Mean pulmonary arterial and peak airway pressures increased significantly after protamine reversal in goat. On the other hand, in rabbit and human, mean pulmonary arterial and peak airway pressures showed no significant changes. Goat was far more sensitive to protamine reversal than rabbit and human. We conclude that PIM may be the main cause of the pulmonary reaction after protamine reversal.