High frequency oscillatory ventilation has been shown to improve oxygenation of patients with severe respiratory failure. This prospective study examined the potential benefits and risks of the latest generation high frequency oscillatory ventilator (R100, Metran, Saitama, Japan), initiated when the target oxygenation could not be achieved by conventional mechanical ventilation in adult patients with severe hypoxaemic respiratory failure. Thirty-six patients with severe respiratory failure treated with the R100 high frequency oscillatory ventilator were considered. Pneumonia and exacerbation of interstitial pneumonia were the main causes of respiratory failure. The median time on conventional mechanical ventilation or airway pressure release ventilation prior to high frequency oscillatory ventilation was 9.3 hours (interquartile range 4.8 to 25). PaO2/FiO2 at 24 hours after initiation of high frequency oscillatory ventilation was significantly better than the PaO2/FiO2 at baseline (151.2 +/- 61.2 vs. 99.5 +/- 50.0, P = 0.0001). Refractory hypoxaemia within 24 hours was associated with a high risk of mortality (P = 0.0092) and 23 patients (64%), including 11 patients with exacerbation of interstitial pneumonia, died by 30 days. Of the 36 patients included in the study (including one who had developed pneumothorax before high frequency oscillatory ventilation), 12 (33%) developed barotrauma during the course of their intensive care unit stay. In the multivariate analysis, only exacerbation of interstitial pneumonia was a significant risk factor for barotrauma. In summary, the latest generation high frequency oscillatory ventilator could improve oxygenation in adult patients with life-threatening hypoxaemic respiratory failure but the incidence of barotrauma was substantial.