ABSTRACT.The effects of pretreatment with methylprednisolone on the reaction to a toxin isolated from group β-hemolytic streptococci, type III, were studied in seven sheep instrumented for chronic measurements of pulmonary lymph flow and pulmonary artery and left atrial pressure. Each sheep was infused with toxin alone on one day and with methylprednisolone plus toxin on a different day in random order. The toxin alone caused a two-phase reaction. After the infusion of toxin, alone, in the initial phase, pulmonary artery pressure increased from 16 ± 1 to 45 ± 5 mm Hg and the rectal temperature rose from 39.5 ± 0.14 to 40.8 ± 0.18° C. During the second phase, the peripheral blood granulocyte count decreased to 10% of baseline values and the lung lymph protein clearance increased from 5.1 ± 1.1 to 11.2 ± 1.8 ml/h, suggesting increased pulmonary vascular permeability. Methylprednisolone pretreatment did not alter the initial phase of pulmonary hypertension or the febrile response but completely abolished the granulocytopenia and the increased pulmonary vascular permeability. These effects are unlikely to be related to inhibition of prostaglandin synthesis. Prevention of the lung vascular injury by methylprednisolone may be related to inhibition of granulocyte accumulation in the lung.