We studied 16 patients with acute lung injury receiving volume-controlled ventilation to assess the relationships between gas exchange and respiratory mechanics before, during, and after 2 h in the prone position. We measured the end-expiratory lung volume (EELV, helium dilution), the total respiratory system (Cst,rs), the lung (Cst,L) and the thoracoabdominal cage (Cst,w) compliances (end-inspiratory occlusion technique and esophageal balloon), the hemodynamics, and gas exchange. In the prone position, PaO2 increased from 103.2 +/- 23.8 to 129.3 +/- 32.9 mm Hg (p < 0.05) without significant changes of Cst,rs and EELV. However, Cst,w decreased from 204.8 +/- 97.4 to 135.9 +/- 52.5 ml/cm H2O (p < 0.01) and the decrease was correlated with the oxygenation increase (r = 0.62, p < 0.05). Furthermore, the greater the baseline supine Cst,w, the greater its decrease in the prone position (r = 0.82, p < 0.01). Consequently, the oxygenation changes in the prone position were predictable from baseline supine Cst,w (r = 0.80, p < 0.01). Returning to the supine position, Cst,rs increased compared with baseline (42.3 +/- 14.4 versus 38.4 +/- 13.7 ml/cm H2O; p < 0.01), mainly because of the lung component (57.5 +/- 25.1 versus 52.4 +/- 23.3 ml/cm H2O; p < 0.01). Thus, (1) baseline Cst,w and its changes may play a role in determining the oxygenation response in the prone position; (2) the prone position improves Cst,rs and Cst,L when the supine position is resumed.