Whole-body carbon dioxide (CO2) production (RaCO2) is an index of substrate oxidation and energy expenditure; therefore, it may provide information about the metabolic response to sepsis. Using stable isotope techniques, we determined RaCO2 and its relationship to protein and glucose metabolism in medical patients with sepsis and septic shock. Whole-body CO2 production, an index of basal metabolic rate, was measured in 13 patients with sepsis or septic shock and 7 healthy controls using an i.v. infusion of 13C-sodium bicarbonate. Endogenous leucine flux, leucine oxidation, and nonoxidative disposal, indices of whole-body protein breakdown, catabolism, and synthesis, were measured with an infusion of 1-13C-leucine, and glucose production and clearance were measured with an infusion of 2H2-glucose. There was no difference in mean RaCO2 between the patients and controls, but the patients had a wider range of values. The four patients with the lowest RaCO2 died. Protein breakdown and synthesis and glucose production were significantly faster in patients than in controls (P < 0.05). Whole-body CO2 production was positively correlated with protein breakdown (P = 0.001), protein synthesis (P < 0.01), and glucose clearance (P = 0.01). Patients with low metabolic rates (mean-2 SDs of controls) had slower protein breakdown and decreased glucose clearance compared with patients with high metabolic rates (mean + 2 SDs of controls). Septic patients were both hypometabolic and hypermetabolic. The correlation between RaCO2 and protein breakdown and synthesis as well as glucose clearance suggests that RaCO2 can provide information about substrate metabolism in septic patients. Because hypometabolism was associated with mortality and changes in protein and glucose metabolism in septic patients, it may be a useful clinical indicator of an inadequate metabolic response.