The myocardial oxygen consumption (MV˙o ₂) to left ventricular pressure-volume area (PVA) relationship is assumed unaltered by substrates, despite varying phosphate-to-oxygen ratios and possible excess MV˙o ₂ associated with fatty acid consumption. The validity of this assumption was tested in vivo. Left ventricular volumes and pressures were assessed with a combined conductance-pressure catheter in eight anesthetized pigs. MV˙o ₂ was calculated from coronary flow and arterial-coronary sinus O₂ differences. Metabolism was altered by glucose-insulin-potassium (GIK) or Intralipid-heparin (IH) infusions in random order and monitored with [¹⁴C]glucose and [³H]oleate tracers. Profound shifts in glucose and fatty acid oxidation were observed. Contractility, coronary flow, and slope of the MV˙o ₂-PVA relationship were unchanged during GIK and IH infusions. MV˙o ₂ at zero PVA (unloaded MV˙o ₂) was 0.16 ± 0.13 J ⋅ beat^{− 1} ⋅ 100 g^{− 1} higher during IH compared with GIK infusion (P = 0.001), a 48% increase. The study demonstrates a marked energetic advantage of glucose oxidation in the myocardium, profoundly affecting the MV˙o ₂-PVA relationship. This may in part explain the “oxygen-wasting” effect of lipid-enhancing interventions such as adrenergic drugs and ischemia.