In a recent demonstration in anesthetized dogs normal gas exchange was maintained over prolonged periods of time by applying at the airway very high frequency (15 Hz) sinusoidal oscillations with a volume less than half that of the physiologic dead space. Now, 12 patients have been ventilated in this way for as long as 1 hour. All were being mechanically ventilated either following major vascular surgery or for treatment of respiratory failure. Their ages varied from 3 days to 74 years; weights ranged from 2.5 to 100 kg. Oscillatory volumes of 1.5 to 3.0 ml/kg of body weight were delivered using a piston pump operating at a frequency of 15 Hz. Baseline cardiorespiratory data obtained during standard mechanical ventilation were compared to the means of four to six observations obtained during the period of oscillation. The calculated shunt fraction decreased significantly from 12.5 ± 9.1 during mechanical ventilation to 8.2 ± 6.8 during oscillation with no change in either arterial CO2 tensions (37.7 ± 5.0 torr during mechanical ventilation; 37.6 ± 5.4 torr during oscillation) or cardiac output (6.1 ± 2.1 L/min during mechanical ventilation; 6.0 ± 2.3 L/min during oscillation). Two patterns of response were evident. Patients with predominantly right to left shunting (e. g., septic shock) showed little change in calculated Qs/Qt with oscillation. In patients with chronic obstructive lung disease in whom one would expect to have extensive V/Q mismatch, oscillation resulted in large decreases in Qs/Qt ratio (e. g., 25.0 ± 13.0). Oscillatory ventilation appears to be a promising new way of achieving gas exchange with minimal risk of barotrauma to the lung.