The goal of this study was to assess whether serial measurements of regional veno-arterial PcoC2 (VAPco2) and arteriovenous pH (AVpH) differences reflect the onset of tissue hypoxia in various organs during endotoxemia. In 12 anesthetized, mechanically ventilated dogs, ultrasonic flow probes were placed around superior mesenteric, renal, and femoral arteries to measure regional blood flow. The corresponding veins were cannulated for blood sampling. Oxygen uptake (V02) was determined from exhaled gas analysis, and oxygen delivery (D02) was calculated as the product of thermodilution cardiac output and arterial oxygen content. Six dogs served as controls, and six received Escherichia coli endotoxin. Cardiac tamponade was induced to reduce D02. Systemic, mesenteric, and femoral critical D02 (DO2crit) were higher in the endotoxic than in the control group (systemic: 12.1 + or - 2.2 vs. 7.9 + or - 2.6 mL/kg min; mesenteric: 8.2 + or - 2.5 vs. 4.1 + or - .6 mL/100 g tissue-min; femoral: 8.3 + or - 2.3 vs. 4.6 + or - .9 mL/min; all p < .05). Systemic and regional critical oxygen extraction ratio (O2ERcrit) were lower in the endotoxic than in the control group (systemic: 45.1 + or - 9.7 vs. 74.1 + or - 9.1%; mesenteric: 37.1 + or - 15.4 vs. 71.1 + or - 7.4%; renal: 30.7 + or - 24.6 vs. 53.9 + or - 28.7%; femoral: 48.1 + or - 9.2 vs. 75.3 + or - 6.9%; all p < .05). With and without endotoxin, systemic and regional DO2crit calculated from V02, VAPco2, or AVpH were similar. In conclusion, systemic and regional VAPco2 and AVpH gradients can reflect hypoxic threshold in the presence, as in the absence, of endotoxemia.