Acute respiratory failure (ARF) following trauma or sepsis has a mortality rate of 50% to 85%. The mainstays of treatment are mechanical ventilation and positive end-expiratory pressure (PEEP). In the past decade, many reports have claimed superiority of high frequency ventilation (HFV) in the treatment of ARF. We structured a prospective randomized trial of HFV versus conventional mechanical ventilation (CMV) in the treatment of acute respiratory failure. All patients admitted to the Surgical Intensive Care Unit (SICU) were eligible for the study. On admission patients identified for being at risk of developing acute respiratory failure were randomized to receive either HFV or CMV. Patients were treated to the same therapeutic endpoint (pH greater than 7.35, PaCO2 35 to 45 torr, PaO2/FIO2 greater than 225). Daily ventilatory support, fluid and drug requirements, and cardiopulmonary variables were recorded. One hundred thirteen patients were entered into the study. Of these, 100 completed the study (HFV n = 52, CMV n = 48) and 60 developed acute respiratory failure (HFV n = 32, CMV n = 28). Patients on HFV reached the therapeutic endpoint at a lower level of continuous positive airway pressure and mean airway pressure; however there were no differences in mortality, SICU days, hospital days, incidence of barotrauma, number of blood gases, or cardiovascular interventions. This report suggests that HFV offers no concrete advantages over CMV when applied in a prospective fashion for the treatment of acute respiratory failure.