This study aimed to apply the dead space fraction [ratio of dead space to tidal volume (VD/VT)] to titrate the optimal positive end-expiratory pressure (PEEP) in a swine model of acute respiratory distress syndrome (ARDS). Twelve swine models of ARDS were constructed. A lung recruitment maneuver was then conducted and the PEEP was set at 20 cm H2O. The PEEP was reduced by 2 cm H2O every 10 min until 0 cm H2O was reached, and VD/VT was measured after each decrement step. VD/VT was measured using single-breath analysis of CO2, and calculated from arterial CO2 partial pressure (PaCO2) and mixed expired CO2 (PeCO2) using the following formula: VD/VT = (PaCO2 - PeCO2)/PaCO2. The optimal PEEP was identified by the lowest VD/VT method. Respiration and hemodynamic parameters were recorded during the periods of pre-injury and injury, and at 4 and 2 cm H2O below and above the optimal PEEP (Po). The optimal PEEP in this study was found to be 13.25±1.36 cm H2O. During the Po period, VD/VT decreased to a lower value (0.44±0.08) compared with that during the injury period (0.68±0.10) (P<0.05), while the intrapulmonary shunt fraction reached its lowest value. In addition, a significant change of dynamic tidal respiratory compliance and oxygenation index was induced by PEEP titration. These results indicate that minimal VD/VT can be used for PEEP titration in ARDS.