We compared computer-controlled mechanical ventilation programmed for biologic variability of respiratory rate (RR) and tidal volume (VT) with conventional intermittent positive-pressure ventilation (IPPV) in an oleic acid (OA) lung injury model. Seventeen pigs were ventilated with an Ohio 7000 anesthesia ventilator. Minute ventilation (VE) was adjusted to maintain PaCO2 at 30 to 35 mm Hg at baseline and was not altered further. OA was infused at 0.2 ml/kg/h until PaO2 decreased to < 125 mm Hg (F(I)O2 = 0.5). Animals were randomly assigned to continue with conventional IPPV (control group; n = 8) or had IPPV computer-controlled (computer group; n = 9). Hemodynamic, respiratory gas, airway pressure, and volume data were obtained at baseline (before OA infusion), at Time 30 (after infusion), and at 30-min intervals for 240 min after OA. At experiment completion, the lungs were removed to determine the wet:dry weight ratios. The control group had RR fixed at 20 breaths/min. The computer group had a RR of 20 +/- 2.3 breaths/min (range, 15 to 27 breaths/min), comprising 369 different RR values with reciprocal changes in VT over 1,089 s before the program looped to repeat itself. There was no difference between groups in the volume of OA infused. By 120 min after lung injury, animals in the computer group had significantly greater PaO2, associated with a lower Qs/QT. Mean airway pressures and mean peak airway pressures were not different in the two groups. By 180 min, respiratory system compliance (Crs) was significantly lower in the control group. The wet:dry lung weight ratios were greater in the control group. Thus, in a porcine model of OA lung injury, computer-controlled mechanical ventilation, which is programmed for biologic variability, resulted in improved blood oxygenation without increasing mean airway pressures when compared with conventional IPPV.