BACKGROUND: Prone position and PEEP can both improve oxygenation and other parameters, but their interaction has not been fully described. Limited data directly compare selection of mechanically "optimal" or "best" PEEP in both supine and prone positions, either with or without changes in chest wall compliance. To compare best PEEP in these varied conditions, we used an experimental ARDS model to compare the mechanical, gas exchange, and hemodynamic response to PEEP titration in supine and prone position with varied abdominal pressure. METHODS: Twelve adult swine underwent pulmonary saline lavage and injurious ventilation to simulate ARDS. We used a reversible model of intra-abdominal hypertension to alter chest wall compliance. Response to PEEP levels of 20,17,14,11, 8, and 5 cmH2O was evaluated under four conditions: supine, high abdominal pressure; prone, high abdominal pressure; supine, low abdominal pressure; and prone, low abdominal pressure. Using lung compliance determined with esophageal pressure, we recorded the "best PEEP" and its corresponding target value. Data were evaluated for relationships among abdominal pressure, PEEP, and position using three-way analysis of variance and a linear mixed model with Tukey adjustment. RESULTS: Prone position and PEEP independently improved lung compliance (P < .0001). There was no interaction. As expected, intra-abdominal hypertension increased the PEEP needed for the best lung compliance (P < .0001 supine, P = .007 prone). However, best PEEP was not significantly different between prone (12.8 +/- 2.4 cmH2O) and supine (11.0 +/- 4.2 cmH2O) positions when targeting lung compliance CONCLUSIONS: Despite complementary mechanisms, prone position and appropriate PEEP exert their positive effects on lung mechanics independently of each other.