In a porcine endotoxin shock model, the mixed nonpeptide endothelin receptor antagonist bosentan was administered 2 h after onset of endotoxemia (n = 8). Cardiopulmonary vascular changes, oxygen-related variables, and plasma levels of endothelin-1-like immunoreactivity were compared with a control group that received only endotoxin (n = 8). Bosentan abolished the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance seen in controls. Possible mechanisms include blockade of vasoconstrictive endothelin receptors, and a lesser degree of edema and inflammation indicated by less alveolar protein and a lower inflammatory cell count observed in bronchoalveolar lavage. Further, bosentan restored cardiac index to the pre-endotoxin level by an increase in stroke volume index, improved systemic oxygen delivery, and acid base balance. Because mean arterial blood pressure was unaffected, bosentan reduced systemic vascular resistance. Endotoxemia resulted in an increase in tumor necrosis factor-alpha and endothelin-1-like immunoreactivity plasma levels, the latter being further increased by bosentan. In conclusion, in porcine endotoxemia, treatment with the endothelin receptor antagonist bosentan, administered during fulminate shock, abolished pulmonary hypertension and restored cardiac index. These findings suggest that bosentan could be an effective treatment for reversing a deteriorated cardiopulmonary state during septic shock.