Rapid infusion of intravenous saline, a model of pulmonary interstitial edema, alters the distribution of pulmonary perfusion, raises pulmonary capillary blood volume, and increases bronchial wall thickness in humans. We hypothesized that infusion would disrupt pulmonary gas exchange by increasing ventilation/perfusion (V̇a/Q̇) inequality as opposed to a diffusive impairment in O₂ exchange. Seven males (26 ± 3 yr; FEV1: 110 ± 16% predicted.) performed spirometry and had V̇a/Q̇ mismatch measured using the multiple inert gas elimination technique, before and after 20 ml/kg iv of normal saline delivered in ∼30 min. Infusion increased thoracic fluid content from transthoracic impedance by 12% (P < 0.0001) and left FVC unchanged but reduced expiratory flows (FEF_25–75 falling from 5.1 ± 0.4 to 4.2 ± 0.4 l/s, P < 0.05). However, V̇a/Q̇ mismatch as measured by the log standard deviation of the ventilation (LogSDV̇) and perfusion (LogSDQ̇) distributions remained unchanged; LogSDV̇: 0.40 ± 0.03 pre, 0.38 ± 0.04 post, NS; LogSDQ̇: 0.38 ± 0.03 pre, 0.37 ± 0.03 post, NS. There was no significant change in arterial Po₂ (99 ± 2 pre, 99 ± 3 mmHg post, NS) but arterial Pco₂ was decreased (38.7 ± 0.6 pre, 36.8 ± 1.2 mmHg post, P < 0.05). Thus, infusion compressed small airways and caused a mild degree of hyperventilation. There was no evidence for a diffusive limitation to O₂ exchange, with the measured-predicted alveolar-arterial oxygen partial pressure difference being unaltered by infusion at Fi_O2 = 0.125 (4.3 ± 1.0 pre, 5.2 ± 1.0 post, NS). After infusion, the fraction of perfusion going to areas with V̇a/Q̇ < 1 was increased when a subject breathed a hyperoxic gas mixture [0.72 ± 0.06 (Fi_O2 = 0.21), 0.80 ± 0.06 (Fi_O2 = 0.30), P < 0.05] with similar effects on ventilation in the face of unchanged V̇a and Q̇. These results suggest active control of blood flow to regions of decreased ventilation during air breathing, thus minimizing the gas exchange consequences.