Controlled 24 and 96 hour experiments compared the efficacy of HFV and an intermittent "sigh" to PPV/PEEP in the management of premature baboons with HMD. Twenty-five animals were delivered by hysterotomy at 140+/−3 days, resuscitated and managed with conventional ICU techniques. Ten of the animals were placed on either HFV or PPV and sacrificed after 24 hours. The a/A ratio was maximized by adjustment of the MAP. Frequency was kept at 10Hz in the HFV animals and pCO2 regulated by adjustment of VT. The a/A ratio was higher and mean airway pressure (MAP) lower in the HFV animals during the 24 hr period. Lungs of the HFV baboons were more evenly aerated at necropsy. Fifteen additional prematures were ventilated for 96 hours using an oscillator (HFO) or flow interrupter (HFFI) at 10Hz or PPV/PEEP. Clinical management was as in the first experiment. a/A ratios were higher and MAP lower in the high frequency groups in the first 48 hours; these differences were not present by 96 hours. In both experiments, HFFI resulted in better oxygenation at lower pressures than did either HFO or PPV, but led to more pressure-related lung injury. Animals ventilated with HFO had an abundance of active type II pneumocytes with a stratified surface layer. Hepatic derangement was also seen in this group. These studies suggest that HFV with an appropriate strategy decreases both oxygen and pressure exposure early in the course of HMD.