Ventilatory requirements using high-frequency oscillation (HFO) during simulated altitude exposure were investigated in control dogs and animals with oleic acid-induced lung injury. FIO2 values of 0.21 and 1.0 were supplied by bias flow to the normal and injured dogs, respectively. After a control period, animals were exposed to a simulated altitude of 8,000 ft (barometric pressure 564 torr), followed by a second control period at ground level. Both experimental groups had similar values of PaCO2 at ground level and during exposure to reduced barometric pressure. The tidal volume necessary to maintain eucapnia was higher in oleic acid-injured animals compared with the control group; cardiac output and functional residual capacity were lower. The alveolar-arterial oxygen difference was substantially larger in the oleic acid group. Adequate gas exchange can be maintained with HFO during exposure to altitude provided that ventilation and inspired PO2 are not reduced below normobaric levels.