OBJECTIVE: To assess the effect of endotoxin on cytochrome aa3 (Caa3) redox status in a controlled blood flow preparation of pig isolated hindlimb, at a constant oxygen delivery (Do2limb) (constant flow period) and during progressive ischemia (decreasing flow period). DESIGN: Randomized, controlled experimental study. SETTING: University hospital experimental laboratory. SUBJECTS: Ten piglets. INTERVENTIONS: Hindlimb blood flow was restricted to the femoral vessels. The arterial femoral blood flow coming from the carotid artery was controlled by a roller occlusive pump. The femoral venous blood flow was returned to the jugular vein. During the first 100 mins, the hindlimb blood flow was maintained at a normal level and then decreased stepwise. Animals were randomized to receive 150 microg/kg endotoxin lipopolysaccharide (LPS; n = 5) or saline (control; n = 5). MEASUREMENTS AND MAIN RESULTS: Hindlimb muscle Caa3 redox status was monitored by near-infrared spectroscopy. Hindlimb Do2limb and oxygen consumption (Vo2limb) were calculated. In the LPS group, a rapid reduction of Caa3 redox status was observed after LPS administration, whereas the hindlimb blood flow remained normal with no change in Do2limb and Vo2limb. A progressive simultaneous decrease in Do2limb and Vo2limb was observed during the decreasing flow period with no further reduction in Caa3 redox status. In the control group, no change was observed in Caa3, Do2limb, or Vo2limb during the constant flow period. During the decreasing flow period, Caa3 redox status was reduced as Do2limb and Vo2limb decreased. CONCLUSION: Our results suggest that endotoxin may induce a reduction of Caa3 redox status independently of Do2 and Vo2.