Inhalation of perfluorohexane vapor (PFH) and high-frequency oscillatory ventilation (HFOV) both have been shown to improve lung function in acute lung injury (ALI). Their combination implies synergistic action. The authors investigated technical aspects of PFH vaporization during HFOV and effects on gas exchange in a pilot study of experimental ALI. Eighteen anesthetized sheep were randomly assigned to HFOV or HFOV with PFH inhalation after oleic acid-induced ALI. HFOV was set to a continuous distending pressure of 25 cm H₂O, and an oscillation of 80 to 100 cm H₂O at a frequency of 5 Hz. PFH vapor was delivered by means of bypassed high-flow oxygen through a thin endotracheal tube. PFH concentration was measured by infrared absorption. Blood gases and hemodynamic data were taken. PaO₂ significantly increased from 9.1 ± 0.9 to 32.7 ± 9.5 kPa (mean ± SEM) in the HFOV group and from 12.5 ± 1.1 to 27.0 ± 6.8 kPa in the HFOV PFH group. PaCO₂ significantly decreased from 6.3 ± 0.3 to 5.5 ± 0.5 kPa in the HFOV group and from 5.7 ± 0.4 to 4.9 ± 0.5 kPa in the HFOV PFH group. Changes in gas exchange were not different between groups. These results show that the inhalation of PFH during HFOV is technically feasible, but did not enhance gas exchange in a 210-minute observation period of experimental ALI.