We studied the effects of an artificial surfactant, Exosurf, administered as an aerosol on respiratory system compliance (Crs), total respiratory resistance (RT), and gas exchange (PO2) in anesthetized, paralyzed sheep with oleic acid (OA)-induced lung injury. Paired experiments with OA were performed in 10 sheep, 5 of which received Exosurf in the first experiment and aerosolized 0.9% NaCl in the second; in the other 5 sheep the order of Exosurf and NaCl was reversed. Paired experiments without OA were performed in 6 additional sheep that served as controls. In the first set of experiments, OA caused significant abnormalities, compared to control and baseline values (p less than 0.02), in Crs, RT, and PO2; there was no difference between animals that received Exosurf and those that received NaCl. Baseline values for PO2 and Crs during the second set of experiments with OA were lower than controls (p less than 0.002), indicating that the animals had not fully recovered from their initial injury. After OA, the animals that received NaCl (i.e., the ones that received Exosurf the first time) had higher PO2 and Crs values (p less than 0.01) than those that received NaCl first and Exosurf second. There was no difference in postmortem lung water content between the animals that received Exosurf or NaCl first, both of which were higher than control (p less than 0.01). Studies in 3 additional sheep showed peripheral deposition of aerosol. Thus, we failed to show an acutely beneficial effect of aerosolized Exosurf in OA-induced lung injury; Exosurf did, however, appear to provide protection against some of the consequences of repeated lung injury.