Background: In ventilated patients, PEEP can be applied to establish a positive transpulmonary pressure (airway minus pleural pressure, Ptp) and maintain open lungs. However, Ptp is usually determined while supine and patients are often in other positions. We studied Ptp and lung volume status (functional residual capacity or FRC) in swine placed in different positions. Methods: Twelve anesthetized swine (30-35 kg) were prepared for the protocol by esophageal balloon placement, tracheostomy and chest tube placement to instill liquid and cause a pleural effusion (simulate lung stress). Ventilation was kept constant at VT = 10 ml/kg, f=15, I:E=1:2 and PEEP of 1 and 10 cmH2O (Carestation, GE Healthcare, Madison, WS). Monitoring included Ptp and FRC as unilateral pleural effusion was induced and PEEP of 1 and 10 cmH2O were applied in 5 positions: supine, prone, right lateral, left lateral and fowler's. Results: FRC was increased by PEEP = 10 cmH2O in all positions, as expected (figure). The fowler's position had significantly greater FRC than other tested positions (figure). Mean end-expiratory Ptp in the supine position displayed greater stress (-6.0 cmH2O) than the fowler's (vs. -3.3, p<.001), prone (vs. -4.5, p=.006) or right lateral (vs. -4.7, p<.01) positions. In swine not pre-treated with a fluid bolus, hypotensive episodes were encountered when transferring to the fowler's position. Conclusions: Ptp is affected by positioning and must be considered with caution when avoiding tidal de-recruitment. Supine position was more vulnerable to opening/closing than fowler's, prone or right lateral positions. Fowler's position is recommended to increase lung volume and reduce lung stress, however, blood pressure must be monitored when changing to fowler's. Support provided by HPRF and GE Healthcare.