To compare the ventilation and oxygenation capabilities of jet ventilation at 100 breaths per minute with those of conventional mechanical ventilation (CMV) in adults with respiratory failure, we performed a 2- to 3-h cross-over trial of jet ventilation in 65 stable patients requiring mechanical ventilation. Jet ventilation was delivered with an inspiratory time of 0.2 s through a 1.62-mm injector cannula attached to the proximal endotracheal tube. Drive pressure was adjusted to approximate the arterial PaCO2 on CMV. Measurements of arterial blood gases, peak and mean airway pressures (Paw), blood pressure (BP), and heart rate (HR) were recorded during baseline CMV, after every 30-min period during jet ventilation, and again 30 min after returning the patient to CMV. For analysis, patients were divided into 4 clinical and radiographic patterns: diffuse parenchymal disease (n = 22), focal parenchymal disease (n = 18), obstructive airway disease (n = 6), and nonpulmonary disease (n = 19). Jet ventilation could supply alveolar ventilation comparable to CMV in 58 of the 65 patients. The 7 ventilatory “failures” were characterized by significantly higher minute ventilation requirements, higher levels of PaCO2, higher airway pressures, and smaller PaO2/FlO2 ratios on CMV as compared to the 58 ventilatory “successes.” In the ventilatory “successes,” peak Paw was significantly lower, but mean Paw, PaCO2, PaO2, FlO2, BP, and HR were not significantly different with jet ventilation as compared to CMV. Moreover, in this ventilatory success group, patients with an increase in the PaO2/FlO2 during jet ventilation were not significantly different from patients with a decrease in PaO2/FlO2 in terms of clinical characteristics, ventilation requirements, or gas exchange capabilities on CMV. We conclude that jet ventilation at 100 BPM offers ventilatory support comparable to CMV in most patients but that no significant clinical advantage is provided by this technique in these forms of adult respiratory failure.