Monocrotaline pyrrole (MCTP) is a reactive metabolite of the pyrrolizidine alkaloid monocrotaline. It causes pulmonary lesions associated with pulmonary hypertension and right ventricular hypertrophy. Conditions of exposure to MCTP that result in early lung injury were examined in isolated rat lungs perfused with buffered medium containing 4% bovine serum albumin. When a high, acutely lethal dose (8.1 mg) of chemically synthesized MCTP was added to the 50-ml perfusion medium reservoir, no effects on the perfused lung occurred. However, when the same quantity of MCTP was injected directly into the pulmonary arterial (PA) cannula, the lungs accumulated considerable fluid within 1 h, and this was accompanied by elevated perfusion pressure and elevated lactate dehydrogenase (LDH) activity in the perfusion medium. A lower dose (1.2 mg) of MCTP that is pulmonary hypertensive in vivo also produced edema and elevated perfusion pressure when injected into the PA cannula. Removal of perfused 5-hydroxytryptamine, a function of pulmonary endothelium, was unaltered compared to vehicle-treated control lungs, as was perfusate LDH activity. These results indicate that injury to isolated lungs occurs soon after direct exposure to MCTP, even at a moderate dose that produces primarily delayed effects in vivo.