The response of respiratory gas exchange to incremental increases in positive end-expiratory pressure (PEEP) was studied in patients with the adult respiratory distress syndrome (ARDS). Fifty total changes in PEEP were studied in 19 PEEP trials performed in 16 patients. The initial patterns of ventilation-perfusion distribution as measured by the multiple inert gas elimination technique showed a large shunt flow (32 +/- 14% of total cardiac output), which was accompanied in half of the patients by perfusion to a region of low ventilation-perfusion ratio (VA/Q ratio less than 0.1). In 17 PEEP trials, there was an improvement in PaO2 (increase in PaO2 greater than 10 mmHg over control value) with at least one level of PEEP tested. In the 38 PEEP increments in these trials where PaO2 did improve, there was either a reduction in shunt alone, a reduction in ventilation-perfusion regions alone, or a redistribution in blood flow from shunt to regions of low or normal ventilation-perfusion ratio. In the increments where no increase was observed in PaO2, this reduction in blood flow to shunt or low VA/Q regions did not occur. In some instances, there was an increase in ventilation to unperfused alveoli and evidence of high ventilation-perfusion ratio (VA/Q greater than 10) as the level of PEEP increased. Because patients had an adequate pulmonary artery wedge pressure at the start of the PEEP trial (mean wedge pressure, 12.8 +/- 1.5 mmHg) improvements in oxygenation could usually be attained with only mild decreases in cardiac output.