Observational studies of high-frequency oscillatory ventilation in adults with the acute respiratory distress syndrome have demonstrated improvements in oxygenation. We designed a multicenter, randomized, controlled trial comparing the safety and effectiveness of high-frequency oscillatory ventilation with conventional ventilation in adults with acute respiratory distress syndrome; 148 adults with acute respiratory distress syndrome (Pa_O2/fraction of inspired oxygen ⩽ 200 mm Hg on 10 or more cm H₂O positive end-expiratory pressure) were randomized to high-frequency oscillatory ventilation (n = 75) or conventional ventilation (n = 73). Applied mean airway pressure was significantly higher in the high-frequency oscillation group compared with the conventional ventilation group throughout the first 72 hours (p = 0.0001). The high-frequency oscillation group showed early (less than 16 hours) improvement in Pa_O2/fraction of inspired oxygen compared with the conventional ventilation group (p = 0.008); however, this difference did not persist beyond 24 hours. Oxygenation index decreased similarly over the first 72 hours in both groups. Thirty-day mortality was 37% in the high-frequency oscillation group and was 52% in the conventional ventilation group (p = 0.102). The percentage of patients alive without mechanical ventilation at Day 30 was 36% and 31% in the high-frequency oscillation and conventional ventilation groups, respectively (p = 0.686). There were no significant differences in hemodynamic variables, oxygenation failure, ventilation failure, barotraumas, or mucus plugging between treatment groups. We conclude that high-frequency oscillation is a safe and effective mode of ventilation for the treatment of acute respiratory distress syndrome in adults.