Ventilator settings typically used for high-frequency oscillatory ventilation (HFO) in adults provide acceptable gas exchange but may not take best advantage of its lung-protective aspects. We provide guidelines for HFO in adults with acute respiratory distress syndrome that should optimize the lung-protective characteristics of this ventilation mode. Roundtable discussions, iterative revisions, and consensus. Five academic medical centers. Not applicable. Participants addressed how to best maintain ventilation through combinations of oscillation pressure amplitude, frequency, and the use of an endotracheal tube cuff leak, and to maintain oxygenation through combinations of recruitment maneuvers, mean airway pressure, and oxygen concentration. The guiding principles were to provide lung protective ventilation by minimizing the size of tidal volumes, and balance the risks and benefits of lung recruitment and distension. HFO may provide smaller tidal volumes and more complete lung recruitment than conventional modes. To optimize these features, we recommend use of the maximum pressure-oscillation amplitude coupled with the highest tolerated frequency, targeting a pH of only 7.25-7.35. This will yield a smaller tidal volume than typical HFO settings where frequency is limited to 6 Hz or less and pressure amplitude is submaximal. Lung recruitment can be achieved with the use of recruitment maneuvers, especially during the first several days of HFO. Recruitment may be augmented or sustained with generous mean airway pressures. These may either be chosen from a table of recommended mean airway pressure and oxygen concentration combinations, or individually titrated based on the oxygenation response of each patient. Modification of the goals and tactics of HFO use may better protect against ventilator-associated lung injury. Further clinical trials are needed to compare the effects on patient outcome of the best use of HFO compared to the most protective use of conventional modes in adult acute respiratory distress syndrome.