We examined serial changes in total body oxygen consumption (Vo2) in a permanently tracheotomized canine sepsis model. On Day 0, beagles had an Escherichia coli-infected (septic) or sterile (control) clot surgically placed in the peritoneum. During the 21-d study, 10 of the 16 septic animals and none of the six control animals died (p = 0.02). After clot placement septic versus control animals had decreased mean arterial blood pressure (mm Hg; Day 1: 106 versus 128, p = 0.055; Day 2: 95 versus 125, p = 0.004, respectively) and left ventricular ejection fraction (Day 1: 0.44 versus 0.69, p = 0.0006; Day 2: 0.33 versus 0.57, p = 0.0001, respectively). Despite significant lethality and cardiovascular dysfunction, in the septic group on Days 1 and 2, septic versus control animals had no significant differences in mean metabolic cart measured (Vo2DIR, ml/kg/min; Day 1: 11.9 versus 12.4, p = 0.81; Day 2: 14.2 versus 13.5, p = 0.72, respectively) and intravascular catheter calculated (Vo2INDIR, ml/kg/min; Day 1: 11.2 versus 11.2, p = 0.99; Day 2: 12.8 versus 15.4, p = 0.49, respectively). On Day 1 in septic and control animals, volume infusion produced increases (p < 0.001) in oxygen delivery (Do2). In septic and control animals these changes in Do2 were similar and were associated with similar increases in Vo2DIR (p = 0.001), and Vo2INDIR (p = 0.001). In fact, at all time points studied (baseline, Day 1, 2, and 21), both before and after volume infusion, levels of Do2, Vo2DIR, and Vo2INDIR did not differ between septic and control animals, nor did they differ between septic survivors and nonsurvivors. Because levels of Vo2DIR and Vo2INDIR were similar in both groups, we pooled data from septic and control animals. Throughout the study, Vo2 showed a moderate association with Vo2INDIR (r = 0.55, p = 0.003), but mean Vo2DIR was lower at baseline (p = 0.001) and on Day 21 (p = 0.07) and greater on Day 2 (p < 0.01). In summary, our techniques, which detected small changes in both Vo2DIR and Vo2INDIR occurring with volume infusion, did not demonstrate differences in these parameters comparing control and septic animals. These results in euvolemic septic animals suggest that total body Vo2 may not reflect pathogenetic mechanisms during sepsis and septic shock. Furthermore, these results suggest that although the level of total body Vo2 may reflect the effects of therapeutic interventions such as volume loading, it should not itself serve as a therapeutic target.