Beneficial anti-inflammatory properties have been ascribed to volatile anesthetics in septic conditions, but no studies have compared anesthesia to the conscious state in a large-animal model. The aim of this study was to investigate the effect of isoflurane anesthesia on cardiovascular and respiratory function, leukocyte activation, and lung damage in a model of endotoxemia in sheep. Conscious (n = 6) and anesthetized (n = 6) sheep were made endotoxemic by continuous infusion of LPS for 48 h. Central hemodynamics were monitored continuously, and blood samples were collected regularly. Activation of leukocytes was assessed by surface expression of CD11b and plasma myeloperoxidase concentration. Lung damage was determined by electron microscopy, cell count in bronchoalveolar lavage fluid, and analysis of lung vascular permeability. Four additional animals (two conscious and two anesthetized) went through the same protocol but did not receive LPS. LPS infusion induced a hyperdynamic sepsis. The drop in total peripheral resistance was compensated by an increase in heart rate and cardiac output in the conscious group, whereas anesthetized sheep failed to compensate in this way. Endotoxemic isoflurane-anesthetized sheep also showed signs of aggravated lung edema formation and tissue damage together with enhanced neutrophil activation and lung tissue accumulation. Our data suggest that isoflurane in conjunction with mechanical ventilation blunts cardiovascular compensatory mechanisms in sepsis and enhances leukocyte activation, which may contribute to lung edema formation and tissue damage.