We compared biologically variable ventilation (V˙ _bv; n = 9) with control mode ventilation (V˙ _c; n = 8) at low tidal volume (Vt)—initial 6 ml/kg—in a porcine model of acute respiratory distress syndrome (ARDS). Hemodynamics, respiratory gases, airway pressures, and Vt data were measured. Static P-V curves were generated at 5 h. Interleukin (IL)-8 and IL-10 were measured in serum and tracheal aspirate. By 5 h, higher Pa_O2 (173 ± 30 mm Hg versus 119 ± 23 mm Hg; mean ± SD; p < 0.0001 group × time interaction [G × T]), lower shunt fraction (6 ± 1% versus 9 ± 3%; p = 0.0026, G × T) at lower peak airway pressure (21 ± 2 versus 24 ± 1 cm H₂O; p = 0.0342; G × T) occurred with V˙ _bv. IL-8 concentrations in tracheal aspirate and wet:dry weight ratios were inversely related; p = 0.011. With V˙ _c, IL-8 concentrations were 3.75-fold greater at wet:dry weight ratio of 10. IL-10 concentrations did not differ between groups. In both groups, ventilation was on the linear portion of the P-V curve. With V˙ _bv, Vt variability demonstrated an inverse power law indicating fractal behavior. In this model of ARDS, V˙ _bv improved Pa_O2 at lower peak airway pressure and IL-8 levels compared with V˙ _c.