Objective: Maintenance breathing is advocated in mechanical ventilation, which is difficult for the high-frequency oscillatory (HFO) ventilation. To facilitate spontaneous breathing during HFO ventilation, a demand flow system (DFS) was designed. The aim of the present study was to evaluate the system. Design: Animal experiment. Setting: University animal laboratory. Subjects: Eight pigs (47-64 kg). Interventions: Lung injury was induced by lung lavage with normal saline. After spontaneous breathing was restored HFO ventilation was applied, in runs of 30 minutes, with continuous fresh gas flow (CF) or the DFS operated in two different setups. Pressure to regulate the DFS was sampled directly at the Y-piece of the ventilator circuit (DFS) or between the endotracheal tube and measurement equipment at the proximal end of the endotracheal tube. In the end, animals were paralyzed. Breathing pattern, work of breathing, and gas exchange were evaluated. Measurements and Main Results: HFO ventilation with demand flow decreased breathing frequency and increased tidal volume compared with CF. Comparing HFO modes CF, DFS, and DFSPROX, total pressure-time product (PTP) was 66 cm H2O.sec.min(-1) (inter-quartile range 59-74), 64 cm H2O.sec.min(-1) (50-72), and 51 cm H2O.sec.min(-1) (41-63). Ventilator PTP was 36 cm H2O.sec.min(-1) (32-42), 8.6 cm H2O.sec.min(-1) (7.4-10), and 1 cm H2O.sec.min(-1) (-1.0 to 2.8). Oxygenation, evaluated by Pao(2), was preserved when spontaneous breathing was maintained and deteriorated when pigs were paralyzed. Ventilation, evaluated by Pao(2), improved with demand flow. Paco(2) increased when using continuous flow and during muscular paralysis. Conclusions: In moderately lung-injured anesthetized pigs during HFO ventilation, demand flow facilitated spontaneous breathing and augmented gas exchange. Demand flow decreased total breathing effort as quantified by PTP. Imposed work caused by the HFO ventilator appeared totally reduced by demand flow. (Grit Care Med 2009; 37:1068-1073)