Background: Hypoxemia is common during one-lung ventilation (OLV). Atelectasis contributes to the problem. Biologically variable ventilation (BW), using microprocessors to reinstitute physiologic variability to respiratory rate and tidal volume, has been shown to be advantageous over conventional monotonous control mode ventilation (CMV) in improving oxygenation during the period of lung reinflation after OLV in an experimental model. Here, using a porcine model, the authors compared BW with CMV during OLV to assess gas exchange and respiratory mechanics. Methods: Eight pigs (25-30 kg) were studied in each of two groups. After induction of anesthesia-tidal volume 12 ml/kg with CMV and surgical intervention-tidal volume was reduced to 9 ml/kg. OLV was initiated with an endobronchial blocker, and the animals were randomly allocated to either continue CMV or switch to BW for 90 min. After OLV, a recruitment maneuver was undertaken, and both lungs were ventilated for a further 60 min. At predetermined intervals, hemodynamics, respiratory gases (arterial, venous, and end-tidal samples) and mechanics (airway pressures, static and dynamic compliances) were measured. Derived indices (pulmonary vascular resistance, shunt fraction, and dead space ventilation) were calculated. Results: By 15 min of OLV, arterial oxygen tension was greater in the BW group (group x time interaction, P = 0.003), and shunt fraction was lower with BW from 30 to 90 min (group effect, P = 0.0004). From 60 to 90 min, arterial carbon dioxide tension was lower with BW (group x time interaction, P = 0.0001) and dead space ventilation was less from 60 to 90 min (group x time interaction, P = 0.0001). Static compliance was greater by 60 min of BW and remained greater during return to ventilation of both lungs (group effect, P = 0.0001). Conclusions: In this model of OLV, BW resulted in superior gas exchange and respiratory mechanics when compared with CMV. Improved static compliance persisted with restoration of two-lung ventilation.