A single infusion of Perilla ketone (PK) into sheep causes marked increases in lung fluid and solute exchange in the absence of any alteration in either pulmonary arterial or left atrial pressures. These alterations are most compatible with increased pulmonary microvascular permeability. The present paper describes the morphologic changes that accompany the previously described alterations in lung function. In five anesthetized open-chest sheep, lung biopsy tissue was taken at baseline and at 15, 30, 60, 120, and 180 minutes after the start of a single infusion of PK (15-20 mg/kg given over a 20 minute period). Biopsy tissue was taken from different lobes of the lung in random sequence, fixed, and processed for light and electron microscopic examination. Three control sheep received the vehicle, dimethyl sulfoxide, alone. Just 15 minutes after the start of PK infusion, alveolar capillary congestion, accumulation of peripheral lung neutrophils, and intraalveolar and interstitial edema were apparent. Electron microscopy revealed early evidence of damage to both the microvascular endothelial cells and Type I pneumonocytes. The damage became more severe with time. From 30 minutes, occasional nonciliated cells in the airway epithelium exhibited dilated rough and agranular endoplasmic reticulum. Thus, PK causes rapid onset of pulmonary edema accompanied by structural evidence of damage to the microvascular endothelium and Type I pneumonocytes. Pulmonary inflammation was also evident. These structural changes occur before the described alterations in either pulmonary microvascular permeability or reduction in pulmonary compliance.