Oxidative stress, such as increased hydrogen peroxide (H₂O₂) levels, is a major event initiating pathogenesis of various cardiovascular diseases. The effects of Caffeic Acid Phenethyl Ester (CAPE), a natural antioxidant compound, on oxidative stress-induced cardiac cell damage and vascular/heart dysfunction have not been fully elucidated. In this study, the effects of CAPE were tested in H₂O₂-induced H9c2 cell damage, a hind limb ischemia (I, 30 min)/reperfusion (R, 60 min), and a global heart ischemia (I, 30 min)/reperfusion (R, 60 min) conditions. We found that H₂O₂ (300 -700 μM; n=8) concentration-dependently decreased H9c2 cell viability accompanied with increased intracellular reactive oxygen species (ROS). H₂O₂ (500 μM) significantly decreased cell viability to 23 ± 3% with a significantly increased intracellular ROS levels by 2.95 ± 0.6 fold when compared to the control (both p<0.05). By contrast, co-treatment of CAPE (10 to 40 μM) and 500 μM H₂O₂ (n=5) significantly improved cell viability associated with reduction of intracellular ROS in a concentration-dependent manner (p<0.05). Similarly, CAPE (0.95 mg/Kg, equivalent to 40 μM in blood, n=5) when given at reperfusion significantly reduced blood H₂O₂ levels during reperfusion compared to saline treatment in a rat hind limb I (30 min)/R (60 min) model (all p<0.05). Last, CAPE (40 μM, n=5) given at beginning of reperfusion for 5 minutes significantly salvage heart tissue and cardiac contractile function when compared to untreated I/R hearts (n=11; all p<0.05) during 60 min. reperfusion. The cardio-protective effects of CAPE were significantly abolished by a non-selective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (50 μM, n=5), or a heme oxygenase-1 inhibitor, SnPPIX (20 μM, n=5) (all p<0.05). These results suggest that CAPE mitigates H₂O₂ caused cardiac cell damage and I/R induced vascular and heart dysfunction possibly by reducing oxidative stress and/or increasing heme oxygenase-1 and nitric oxide synthase activity.