OBJECTIVE: To describe improved ventilation during high-frequency oscillatory ventilation when a nitrogen-oxygen gas mixture is replaced by a helium-oxygen gas mixture. DESIGN: Case series. SETTING: A tertiary pediatric intensive care unit. PATIENTS: Five patients with hypoxemic respiratory failure who developed persistent respiratory acidosis during treatment with high-frequency oscillatory ventilation. INTERVENTIONS: Introduction of helium-oxygen into a conventional high-frequency oscillatory ventilation circuit. MEASUREMENTS AND MAIN RESULTS: Blood gas values (pH, Pco2, and Po2) were compared in these patients during treatment with high-frequency oscillatory ventilation with nitrogen-oxygen gas flow and then for several hours after a change in treatment to helium-oxygen gas flow. An initial 24% decrease in Pco2 was documented, and an ultimate 43% decrease in Pco2 was observed. The mechanism for this improved ventilation may be related to improved gas flow properties as well as increased CO2 diffusion resulting from helium's low-mass density. Oxygenation was not adversely affected in any way. CONCLUSION: In patients with hypoxemic respiratory failure and in whom respiratory acidosis develops during high-frequency oscillatory ventilation, the use of helium-oxygen rather than nitrogen-oxygen may improve ventilation and decrease ventilator-related trauma. Further investigation is needed to validate these findings and to elucidate the mechanisms of improved ventilation.