Objective: To evaluate and compare the effect of tracheal gas insufflation using two gases with different physical properties, helium and oxygen, as an adjunct to conventional mechanical ventilation in patients with respiratory failure. Design: Prospective, intervention study. Setting: General intensive care unit in a tertiary university medical center. Patients: Seven sedated and paralyzed patients with respiratory failure of various etiologies. All patients were ventilated in the volume control mode (tidal volume 5 to 7 mL/kg). Inclusion criteria were Paco(2) of greater than or equal to 50 torr (greater than or equal to 6.7 kPa), together with peak inspiratory pressure of greater than or equal to 35 cm H2O and respiratory rate of greater than or equal to 14 breaths/min. Interventions: All patients were intubated with an endotracheal tube that had an additional lumen opening at its distal end, through which tracheal gas insufflation was administered. The tracheal gas insufflation was applied continuously throughout the respiratory cycle at three flow rates (2, 4, and 6 L/min) with two gases, oxygen and helium, while the ventilatory settings were main maintained constant. Measurements and Main Results: In addition to airway pressures and arterial blood gases, the relative efficacy of tracheal gas insufflation with each gas was estimated using a "coefficient of efficiency" (which we defined as the change in Paco(2)/peak inspiratory pressure) compared with baseline measurements. Tracheal gas insufflation with both gases decreased Paco(2) significantly (p<.05) at all flow rates. This effect was accompanied by an increase in airway pressure with both gases (oxygen and helium). However, at flow rates of 6 L/min, tracheal gas insufflation with helium resulted in lower peak inspiratory pressure than with oxygen. Tracheal gas insufflation with helium was more effective (as estimated by the coefficient of efficiency) than with oxygen at all flow rates (p<.05). Conclusion: In volume-controlled, mechanically ventilated patients with respiratory failure, tracheal gas insufflation with helium might be suggested as an alternative to oxygen.