The exact mechanism linking the systemic inflammatory response associated with sepsis to changes in lung function remains to be determined. In a human experimental model of inflammation, we investigated how acute systemic and local pulmonary inflammation affects ventilatory capacity and pulmonary gas exchange. Fifteen volunteers received Escherichia coli lipopolysaccharide (LPS) intravenously or endobronchially on two different study days. Blood samples were obtained hourly (t = 0-8 h) and spirometry was performed at baseline and after 8 h. Both interventions decreased ventilatory capacity compared to baseline (p < 0.01), and this was more pronounced after intravenous (forced expiratory volume in 1-s, FEV1 ; 0.6 L/12% reduction) compared to endobronchial (FEV1 ; 0.32 L/7% reduction) administration (p < 0.05). Furthermore, the alveolar-arterial oxygen difference increased after intravenous but not after endobronchial endotoxin. These findings indicate that pulmonary gas exchange is impaired to a greater extent during endotoxin-induced systemic inflammation than during endotoxin-induced local pulmonary inflammation.