Although it has been shown in normal subjects that airway resistance changes significantly with changes in lung volume and inspiratory flow, no studies have as yet examined these phenomena in patients with adult respiratory distress syndrome (ARDS). The effect of positive end-expiratory pressure (PEEP) on airway resistance in ARDS also is unknown. We have used the technique of rapid airway occlusion during constant-flow inflation to measure the interrupter resistance (Rint,rs), which in humans is thought to correspond to airway resistance, in nine patients with ARDS under different inflation flows and volumes. This procedure was carried out at four levels of PEEP (0, 5, 10, and 15 cm H2O). We found that (1) at constant inflation volume, Rint,rs did not change significantly with increasing flow; (2) at constant inflation flow, Rint,rs showed an initial decrease followed by a distinct rise with increasing lung volume; (3) on average, PEEP did not significantly change Rint,rs measured during baseline ventilation; and (4) this latter finding occurred because patients behaved differently with application of PEEP, depending on their degree of lung inflation: Rint,rs measured close to full inflation almost invariably exhibited a rise, but values obtained at lower volumes exhibited the characteristic decrease of Rint,rs with increasing inflation volume.