Purpose: A quantitative measure of the airway pressure-time tracing during passive inflation [stress index (SI)] has been suggested as an indicator of tidal lung recruitment and/or overinflation. If reliable, this simple index could help guide positive end-expiratory pressure (PEEP) and tidal volume selection. The compartment surrounding the lungs should impact airway pressure and could, therefore, affect SI validity. To explore the possibility, we determined SI in a swine model of pleural effusion (PLEF). Methods: Unilateral PLEF was simulated by instilling fluid (13 ml/kg-moderate, 26 ml/kg-large) into the right pleural space of five anesthetized, paralyzed, mechanically ventilated pigs. Animals were ventilated with constant flow ventilation: tidal volume (V-T) 9 ml/kg, f set to end-tidal CO2 (ETCO2) of 30-40 mmHg, inspiratory to expiratory ratio (I/E) 1:2, PEEP 1 or 10 cmH(2)O. Respiratory system mechanics and computed tomography (CT) were acquired at end-inspiration and end-expiration to determine % tidal recruitment and overinflation. Results: Prior to PLEF instillation, SI values derived at PEEP = 1 and 10 cmH(2)O were 0.90 and 1.22, respectively. Moderate PLEF increased these SI values to 1.06 and 1.24 and large PLEF further increased SI to 1.23 and 1.27 despite extensive tidal recruitment and negligible overdistention by CT. The initial half of the tidal pressure curve produced SI values (range 0.82-1.17) that were significantly lower than those of the second half (0.98-1.37). Conclusions: In the presence of pleural fluid, SI indicated overinflation when virtually none was present and tidal lung recruitment predominated. When the extrapulmonary environment is abnormal, caregivers are advised to interpret the SI with caution.