Background: Rodent studies suggest that peroxisome proliferator-activated receptor-alpha (PPAR-) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR- activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR- activator fenofibrate affects myocardial I/R injury in pigs. Methods: Domestic farm pigs were assigned to treatment with fenofibrate 50 mg/kg/d orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 weeks, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized, open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to raise arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Results: Plasma concentration of fenofibric acid was similar to the EC₅₀ for activation of PPAR- in vitro and to maximal concentration achieved in clinical use. Myocardial expression of PPAR- mRNA was prominent, but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyl transferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each p<0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low-fat or high-fat group, nor did it affect myocardial infarct size. Conclusion: Despite expression of PPAR- in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR- activator does not alter myocardial metabolic or contractile responses to I/R in pigs.