The effect of perfluorochemical (PFC) blood substitutes on arterial endothelium following total blood replacement was evaluated. Conscious female Sprague-Dawley rats (150-200 gms) were isovolumically exchange perfused with 3 blood volumes of PFC emulsion in an O2 chamber. The exchange was performed at 0.5 ml/min via an indwelling-intracardiac-double-lumen catheter. One hour after the exchange, the animal was sacrificed and the circulatory system flushed free of blood and PFC emulsion with Dulbecco''s solution, followed by perfusion fixation with glutaraldehyde solution. The heart, lungs and thoracic aorta were excised. The pulmonary arterial endothelial cell response was determined by scanning electron microscopy (SEM) following acute exposure to PFC emulsions under conditions of varied pH, oncotic pressure and emulsion age. These endothelial surfaces exhibited increased microvilli, leukocyte adhesion, fibrin deposition and subendothelium exposure. The magnitude of these abnormal responses varied with the degree of alkalinity and reduced oncotic pressure of the perfusate.