High levels of fatty acids can decrease the recovery of previously ischemic hearts by inhibiting myocardial glucose use during reperfusion. We determined if this was due to a decrease in glycolysis or a decrease in glucose oxidation. Isolated working rat hearts were perfused with either 11 mM [2-3H/U-14C] glucose or 11 mM [2-3H/U-14C] glucose and 1.2 mM palmitate. In aerobically perfused hearts, the presence of fatty acids reduced glucose oxidation rates (from 1576 +/- 154 to 228 +/- 28 nmol/min.g dry weight, P < .05), with a nonsignificant reduction in glycolysis (from 3297 +/- 349 to 2798 +/- 343 nmol/min.g dry weight). If fatty acid perfused hearts were subjected to a 30-min period of ischemic function was 36%. Glucose oxidation rates during reperfusion were markedly lower than glycolytic rates (228 +/- 35 and 3096 +/- 576 nmol/min.g dry weight, respectively, P < .05). Dichloroacetate (1 mM) added during reperfusion significantly improved recovery of mechanical function to 96% of preischemic values. In these hearts, Dichloracetate increased glucose oxidation, while actually decreasing glycolytic rates (values during reperfusion were 501 +/- 136 and 1171 +/- 122 nmol/min.g dry weight, respectively). Insulin (500 microU/ml) added at reperfusion resulted in a small increase in glucose oxidation rates and a significant increase in glycolysis (375 +/- 66 and 4769 +/- 955 nmol/g dry weight.min, respectively). However, the presence of insulin at reperfusion did not improve recovery of function (hearts recovered 52% of preischemic function). We demonstrate that the detrimental effects of high concentrations of fatty acids after ischemia are primarily due to an inhibition of glucose oxidation, and not glycolysis, during the reperfusion period. Furthermore, increasing glucose oxidation during reperfusion has a beneficial effect on functional recovery of hearts.