Metabolic and hemodynamic measurements performed in 72 septic (S) and 40 nonseptic (NS) surgical patients undergoing total parenteral nutrition were analyzed to assess the role of substrate supply as a determinant of O2 extraction (O2Ex). In S, O2Ex was inversely related to cardiac index (CI); at any given CI, significant increases in O2Ex with simultaneous increases in O2 consumption (VO2) were related to increasing doses of amino acids, with a less remarkable effect of fat and no effect of glucose dose. In NS, O2Ex was also inversely related to CI; however, at any given CI, there was no evident substrate-supply dependency of O2Ex, which was more normally related to P50. The increase in VO2 per gram of administered amino acids, at any CI and O2 transport index, was 817 ml in S and 267 ml in NS. These results suggest that the impaired O2Ex and VO2 in S may at least partly reflect abnormalities in substrate utilization and that amino acid support may have a role in modulating these abnormal O2Ex patterns by providing preferential substrate for oxidative metabolism.