In acute respiratory distress syndrome, alveolar recruitment improves gas exchange only if perfusion of the recruited alveolar units is adequate. To evaluate functional recruitment induced by positive end-expiratory pressure, we assessed pulmonary conductance for gas exchange based on lung diffusion for carbon monoxide and its components, including pulmonary capillary blood volume. Prospective, randomized, crossover study. Medical intensive care unit of a university hospital. Sixteen patients with lung injury/acute respiratory distress syndrome as well as eight control patients under invasive ventilation and eight healthy volunteers. Mechanical ventilation with two levels of positive end-expiratory pressure (5 and 15 cm H2O). Lung diffusion for carbon monoxide and lung volumes, arterial blood gas analysis, and pressure-volume curves. In patients with acute respiratory distress syndrome, high positive end-expiratory pressure induced a 23% mean lung diffusion for carbon monoxide increase (4.4 +/- 1.7 mm Hg . min vs. 3.6 +/- 1.4 mL . mm Hg . min). In control patients and in healthy volunteers, lung diffusion for carbon monoxide values were (median interquartile range) 5.5 3.8-8.0 mm Hg . min and 19.6 15.1-20.6 mL . mm Hg . min, respectively. Among patients with acute respiratory distress syndrome, eight showed a >20% lung diffusion for carbon monoxide increase (responders) when increasing positive end-expiratory pressure. In the other eight, lung diffusion for carbon monoxide decreased or showed a <5% increase (nonresponders) with high positive end-expiratory pressure. Compared with nonresponders, responders at low positive end-expiratory pressure had smaller lungs with higher capillary blood volume-to-lung-volume ratio, higher values of the lower inflection point, and significantly greater increases in pulmonary capillary blood volume with high positive end-expiratory pressure. High positive end-expiratory pressure increased PaO2/Fio2 only in the responders. The functional response to positive end-expiratory pressure in patients with acute lung injury/acute respiratory distress syndrome seems better when the lungs are smaller and with a higher capillary blood-volume-to-lung-volume ratio. Lung diffusion for carbon monoxide measurement supplies additional information about functional lung recruitment, which is not synonymous with mechanical recruitment.