Background: Stress index at post-recruitment maneuvers could be a method of positive end-expiratory pressure (PEEP) titration in acute respiratory distress syndrome (ARDS) patients. However, airway pressure (P-aw) stress index may not reflect lung mechanics in the patients with high chest wall elastance. This study was to evaluate the P-aw stress index on lung mechanics and the correlation between P-aw stress index and transpulmonary pressure (P-L) stress index in acute respiratory failure (ARF) patients. Methods: Twenty-four ARF patients with mechanical ventilation (MV) were consecutively recruited from July 2011 to April 2013 in Zhongda Hospital, Nanjing, China and Ospedale S. Giovanni Battista-Molinette Hospital, Turin, Italy. All patients underwent MV with volume control (tidal volume 6 ml/kg) for 20 min. PEEP was set according to the ARDSnet study protocol. The patients were divided into two groups according to the chest wall elastance/respiratory system elastance ratio. The high elastance group (H group, n = 14) had a ratio >= 30%, and the low elastance group (L group, n = 10) had a ratio <3 0 %. Respiratory elastance, gas-exchange, P-aw stress index, and P-L stress index were measured. Student's t-test, regression analysis, and Bland-Altman analysis were used for statistical analysis. Results: Pneumonia was the major cause of respiratory failure (71.0%). Compared with the L group, PEEP was lower in the H group (5.7 +/- 1.7 cmH(2)O vs. 9.0 +/- 2.3 cmH(2)O, P < 0.01). Compared with the H group, lung elastance was higher (20.0 +/- 7.8 cmH(2)O/L vs. 11.6 +/- 3.6 cmH(2)O/L, P < 0.01), and stress was higher in the L group (7.0 +/- 1.9 vs. 4.9 +/- 1.9, P = 0.02). A linear relationship was observed between the P-aw stress index and the P-L stress index in H group (R-2 = 0.56, P < 0.01) and L group (R-2 = 0.85, P < 0.01). Conclusion: In the ARF patients with MV, P-aw stress index can substitute for P-L to guide ventilator settings.