Clinical studies have demonstrated improved myocardial recovery after severe ischemia in response to acute triiodothyronine (T₃) treatment. We determined whether T₃ improves the recovery of ischemic hearts by improving energy substrate metabolism. Isolated working rat hearts were perfused with 5.5 mM glucose and 1.2 mM palmitate and were subjected to 30 min of no-flow ischemia. Glycolysis, glucose oxidation, and palmitate oxidation were measured during aerobic reperfusion by adding [5-³H]glucose, [U-¹⁴C]glucose, or [9,10-³H]palmitate to the perfusate, respectively. During reperfusion, cardiac work in untreated hearts recovered to a lesser extent than myocardial O₂ consumption (MO₂), resulting in a decreased recovery of cardiac efficiency, which recovered to only 25% of preischemic values. Treatment of hearts with T₃ (10 nM) before ischemia increased glucose oxidation during reperfusion, which was associated with a significant increase in pyruvate dehydrogenase (PDH) activity, the rate-limiting enzyme for glucose oxidation. In contrast, T₃ had no effect on MO₂, glycolysis, or palmitate oxidation. This resulted in a significant decrease in H⁺ production from glycolysis uncoupled from glucose oxidation (2.7 ± 0.3 and 1.9 ± 0.3 µmol · g dry wt¹ · min¹ in control and T₃-treated hearts, respectively, P < 0.05), as well as a 3.2-fold improvement in cardiac work and a 2.3-fold increase in cardiac efficiency compared with untreated postischemic hearts (P < 0.05). These data suggest that T₃ can exert acute effects that improve the coupling of glycolysis to glucose oxidation, thereby decreasing H⁺ production and increasing cardiac efficiency as well as contractile function during reperfusion of the postischemic heart.