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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 …