To test whether perfluorocarbon-associated gas exchange (gas ventilation of the perfluorocarbon-liquid filled lung) could support oxygenation better than conventional positive pressure breathing in a piglet model of gastric aspiration-induced adult respiratory distress syndrome (ARDS). Prospective, randomized, blinded, controlled study. A critical care research laboratory in a university medical school. Fourteen healthy piglets. Under alpha-chloralose anesthesia and metocurine iodide neuromuscular blockade, 14 piglets underwent tracheostomy; central venous, systemic and pulmonary arterial catheterizations; and volume-regulated continuous positive-pressure breathing. Homogenized gastric aspirate (1 mL/kg) titrated to pH of 1.0 was instilled into the tracheostomy tube of each subject at 0 min to induce ARDS. Hemodynamics, lung mechanics, and gas exchange were evaluated every 30 mins for 6 hrs. Seven piglets were treated at 60 mins by tracheal instillation of perflubron, a volume selected to approximate normal functional residual capacity, and were supported by perfluorocarbon-associated gas exchange without modifying ventilatory settings. Perflubron was added to the trachea every hour to replace evaporative losses. There was a significant difference in oxygenation over time when tested by repeated-measures analysis of variance (F test = 8.78, p < .01). On further analysis, the differences were not significant from baseline to 2.5 hrs but became increasingly significant from 2.5 to 6 hrs after injury (p < .05) in the inflammatory phase of gastric aspiration-induced ARDS. Histologic evidence for ARDS in the treated group 6 hrs after injury was lacking. In the piglet model, perfluorocarbon-associated gas exchange with perflubron facilitates oxygenation in the acute phase of gastric aspiration-induced inflammatory ARDS when compared with conventional positive-pressure breathing. Histologic and physiologic data suggest that perfluorocarbon-associated gas exchange with perflubron might prevent ARDS if instituted after aspiration in the time window before the acute inflammatory process is manifest.