Because heliox has a lower density as compared with air, we postulated that heliox would improve gas exchange during high-frequency oscillatory ventilation (HFOV) in a model of acute lung injury. In a prospective, cross-over trial, we studied 11 piglets with acute lung injury created by saline lavage. With initial conditions of permissive hypercapnia (Pa(CO(2)) 55-80 mm Hg), each piglet underwent HFOV with a fixed mean airway pressure, pressure oscillation, and ventilatory frequency. The following gas mixtures were used: oxygen-enriched air (60% O(2)/40% N(2)) and heliox (60% O(2)/ 40% He and 40% O(2)/60% He). Compared with oxygen-enriched air, the 40% and 60% helium gas mixtures reduced Pa(CO(2)) by an average of 10.5 and 20.3 mm Hg, respectively. A modest improvement in oxygenation was seen with the 40% helium mixture. We conclude that heliox significantly improves carbon dioxide elimination and modestly improves oxygenation during HFOV in a model of acute lung injury. On the basis of test lung data and plethysmography measurements, we also conclude that heliox improves carbon dioxide elimination primarily through increased tidal volume delivery. Although heliox improved gas exchange during HFOV in our model, increased tidal volume delivery may limit clinical applicability.