S ince elevation of plasma concentrations of free fatty acids (FFA) increases myocardial oxygen consumption without influencing mechanical performance in normal hearts, it was the purpose of this study to determine whether FFA would modify mechanical performance at limited oxygen supply. Left coronary blood flow was reduced by gradual clamping of a shunt from the left carotid artery until moderate ventricular dilatation supervened. Left ventricular systolic pressure (LVSP), its maximal rate of rise (dP/dt) and stroke volume (SV) were unchanged or slightly reduced. The ischemia resulted in a decrease in myocardial oxygen consumption (MVO₂) from 9.7±1.1 ml/min to 7.9±0.8 ml/min, and myocardial lactate uptake was reduced or reversed to excretion. Increasing the plasma concentrations of FFA from 359±47 μEq/1 to 3688±520 μEq/1 by intravenous infusion of a triglyceride emulsion and heparin resulted in further ventricular dilatation, accompanied by increased excretion of lactate. The ventricular decompensation and enhancement of anaerobic myocardial metabolism associated with increased uptake of FFA was not related to changes in coronary flow, MVO₂, or LVSP. dP/dt and SV were virtually unchanged. Intravenous infusion of glucose/insulin, which lowered plasma concentrations of FFA, reversed ventricular dilatation and lactate excretion.The data support the hypothesis that high concentrations of FFA play a significant role in increasing myocardial oxygen requirement and thereby promote depression of contractility of the hypoxic heart in experimental animals.