BACKGROUND Resveratrol has been shown to reverse some of the detrimental effects of metabolic syndrome (MetS). We sought to define the impact of supplemental resveratrol on normal myocardium remote from an ischemic territory in a swine model of MetS and chronic myocardial ischemia. METHODS Yorkshire swine were fed a normal diet (control), a high cholesterol diet (HCD), or a high cholesterol diet with orally supplemented resveratrol (HCD-R; 100 mg/kg/day). Four weeks after diet modification, myocardial ischemia was induced by ameroid constrictor placement. Seven weeks later, myocardial tissue from a territory remote from the ischemia was harvested. Animals in the HCD and HCD-R groups underwent functional cardiac MRI before ischemia and before sacrifice. Tissue was harvested for protein expression analysis. RESULTS After 7 weeks of ischemia, regional left ventricular systolic function was significantly increased in HCD-R as compared with HCD animals. During ventricular pacing the HCD group had significantly decreased flow (p = 0.03); perfusion in the HCD-R was preserved as compared with the control. There was no difference in microvascular relaxation. Expression of metabolic proteins Sirt-1 (p = 0.002), AMPkinase (p = 0.02), and carnitine palmitoyltransferase-I (p = 0.002) were upregulated in the HCD-R group. Levels of protein oxidative stress were significantly increased in the HCD and HCD-R groups, as compared with the controls (p = 0.003). Activated endothelial nitric oxide synthase (eNOS) was increased in the HCD-R group (p = 0.01). There was no difference in myocardial endothelial cell density between the groups; however, dividing endothelial cells were decreased in the HCD and HCD-R groups (p = 0.006). CONCLUSIONS Resveratrol supplementation improves regional left ventricular function and preserves perfusion to myocardium remote from an area of ischemia in an animal model of metabolic syndrome and chronic myocardial ischemia.