Ventilation-perfusion (V A/Q) distributions were evaluated in 24 patients with acute respiratory distress syndrome (ARDS), during airway pressure release ventilation (APRV) with and without spontaneous breathing, or during pressure support ventilation (PSV). Whereas PSV provides mechanical assistance of each inspiration, APRV allows unrestricted spontaneous breathing throughout the mechanical ventilation. Patients were randomly assigned to receive APRV and PSV with equal airway pressure limits (Paw) (n = 12) or minute ventilation (V E) (n = 12). In both groups spontaneous breathing during APRV was associated with increases (p < 0.05) in right ventricular end-diastolic volume, stroke volume, cardiac index (CI), PaO2, oxygen delivery, and mixed venous oxygen tension (PvO2) and with reductions (p < 0.05) in pulmonary vascular resistance and oxygen extraction. PSV did not consistently improve CI and PaO2 when compared with APRV without spontaneous breathing. Improved V A/Q matching during spontaneous breathing with APRV was evidenced by decreases in intrapulmonary shunt (equal Paw: 33 +/- 4 to 24 +/- 4%; equal V E: 32 +/- 4 to 25 +/- 2%) (p < 0.05), dead space (equal Paw: 44 +/- 9 to 38 +/- 6%; equal V E: 44 +/- 9 to 38 +/- 6%) (p < 0.05), and the dispersions of ventilation (equal Paw: 0.96 +/- 0.23 to 0.78 +/- 0.22; equal V E: 0.92 +/- 0.23 to 0.79 +/- 0.22) (p < 0.05), and pulmonary blood flow distribution (equal Paw: 0.89 +/- 0.12 to 0.72 +/- 0.10; equal V E: 0.94 +/- 0.19 to 0.78 +/- 0.22) (p < 0.05). PSV did not improve V A/Q distributions when compared with APRV without spontaneous breathing. These findings indicate that uncoupling of spontaneous and mechanical ventilation during APRV improves V A/Q matching in ARDS presumably by recruiting nonventilated lung units. Apparently, mechanical assistance of each inspiration during PSV is not sufficient to counteract the V A/Q maldistribution caused by alveolar collapse in patients with ARDS.