Background: During the COVID-19 pandemic, ventilator sharing was suggested to increase availability of mechanical ventilation. The safety and feasibility of ventilator sharing is unknown. Methods: A single ventilator in pressure control mode was used with flow control valves to simultaneously ventilate two patients with different lung compliances. The system was first evaluated using high-fidelity human patient simulator mannequins and then tested for 1 h in two pairs of COVID-19 patients with acute respiratory failure. Patients were matched on positive end-expiratory pressure, fractional inspired oxygen tension, and respiratory rate. Tidal volume and peak airway pressure (PMAX) were recorded from each patient using separate independent spirometers and arterial blood gas samples drawn at 0, 30, and 60 min. The authors assessed acid-base status, oxygenation, tidal volume, and PMAXfor each patient. Stability was assessed by calculating the coefficient of variation. Results: The valves performed as expected in simulation, providing a stable tidal volume of 400 ml each to two mannequins with compliance ratios varying from 20:20 to 20:90 ml/cm H2O. The system was then tested in two pairs of patients. Pair 1 was a 49-yr-old woman, ideal body weight 46 kg, and a 55-yr-old man, ideal body weight 64 kg, with lung compliance 27 ml/cm H2O versus 35 ml/cm H2O. The coefficient of variation for tidal volume was 0.2 to 1.7%, and for PMAX0 to 1.1%. Pair 2 was a 32-yr-old man, ideal body weight 62 kg, and a 56-yr-old woman, ideal body weight 46 kg, with lung compliance 12 ml/cm H2O versus 21 ml/cm H2O. The coefficient of variation for tidal volume was 0.4 to 5.6%, and for PMAX0 to 2.1%. Conclusions: Differential ventilation using a single ventilator is feasible. Flow control valves enable delivery of stable tidal volume and PMAXsimilar to those provided by individual ventilators.