Prolonged exposure to 100% O2 at 1 atm is known to result in a progressive increase of the alveolar epithelial permeability to lipid-insoluble molecules. To investigate whether the damage to the capillary endothelium precedes or follows this event, conscious, unanesthetized rabbits were exposed to 100% O2 from 24 to 66 hr, and (a) the filtration coefficient (Kf) of the pulmonary capillary endothelium in isolated, perfused lungs and (b) the arterial and carbon dioxide gas tensions and right and left heart vascular pressures were measured in intact animals. The mean value of the filtration coefficient (+/- SEM) in air-breathing animals was 0.036 +/- 0.002 ml/(min x Torr x g dry lung). After 48 and 66 hr in 100% O2, it increased by 58 and 114% from its baseline value, respectively. At the later period the lung wet/dry weight of the isolated, but not the intact lungs, increased also from 5.42 +/- .2 to 7.3 +/- .3 (means +/- 1 SEM) due to the combination of a higher capillary conductance and the lack of lymph flow in this preparation. All other variables remained normal throughout the exposure. Thus, in contrast to previous morphological findings, these results indicate that the oxygen damage to the capillary endothelium is progressive and occurs concurrently with the increase of the alveolar permeability to solute but before the appearance of pulmonary edema and the compromise of gas exchange.