In acute respiratory distress syndrome (ARDS), high-frequency oscillation (HFO) improves oxygenation relative to conventional mechanical ventilation (CMV). Alveolar ventilation is improved by adding tracheal gas insufflation (TGI) to CMV. We hypothesized that combined HFO and TGI (HFO-TGI) might result in improved gas exchange relative to both standard HFO and CMV according to the ARDS Network protocol. Prospective, randomized, crossover study. A 30-bed university intensive care unit. A total of 14 patients with early (<72 hrs in duration), severe (PaO2/FiO2 of <150 mm Hg and prerecruitment oxygenation index of 22.8 +/- 1.9 [mean +/- SEM]), primary ARDS. Patients were ventilated with HFO without (60 mins) and combined with TGI (6.1 +/- 0.1 L/min, 60 mins) in random order. HFO sessions were repeated in inverse order within 24 hrs. HFO sessions were preceded and followed by ARDS Network CMV. Four recruitment maneuvers were performed during the study period. During HFO sessions, mean airway pressure was set at 1 cm H2O above the point of maximal curvature of the respiratory system expiratory pressure-volume curve. Gas exchange and hemodynamics were determined before, during, and after HFO sessions. HFO-TGI improved PaO2/FiO2 relative to HFO and CMV (174.5 +/- 10.4 vs. 136.0 +/- 10.0 and 105.0 +/- 3.7 mm Hg, respectively, p < .05 for both) and oxygenation index relative to HFO (17.1 +/- 1.3 vs. 22.3 +/- 1.7, respectively p < .05). PaO2/FiO2 returned to baseline within 3 hrs after HFO. During HFO-TGI, shunt fraction and mixed venous oxygen saturation improved relative to CMV (0.36 +/- 0.01 vs. 0.45 +/- 0.01 and 77.8% +/- 1.2% vs. 71.8% +/- 1.3%, respectively, p < .05 for both). PaCO2 and hemodynamics were unaffected by HFO sessions. Respiratory mechanics remained unchanged throughout the study period. In early onset, primary, severe ARDS, short-term HFO-TGI improves oxygenation relative to standard HFO and ARDS Network CMV.