Ischemia/reperfusion (I/R) has been reported to induce apoptotic cellular death in myocardium. This study tested the hypothesis that caffeic acid phenethyl ester (CAPE), one of the active components of propolis, may ameliorate myocardial apoptosis and oxidative myocardial injury. Wistar rats were divided into 4 groups: (i) sham operated, (ii) I/R, (iii) I/R+CAPE, and (iv) I/R+glutathione (GSH). CAPE (10 micromol/kg) was infused iv 10 min before occlusion of the left anterior descending coronary artery (30 min) followed by reperfusion (120 min). GSH (5 mg/kg) was infused iv after the occlusion and immediately before reperfusion. The TdT-mediated in situ nick end-labeling (TUNEL) method was used to evaluate apoptotic activity. I/R resulted in myocardial apoptosis, alterations of antioxidant status, elevation of serum creatine kinase (CK) and aspartate aminotransferase (AST) activities, evidence of lipid peroxidation, and elevated nitric oxide levels, compared to the sham-operation group. No apoptotic cells were found in the myocardial tissue of sham-operated rats. The TUNEL-positive myocardial cells averaged 60%, 30%, and 40% in the I/R, I/R+CAPE, and I/R+GSH groups, respectively. This study demonstrates that pretreatment with CAPE provides cardio-protection from I/R injury. The I/R+CAPE group showed reduced apoptosis, attenuated NO production, elevated myocardial superoxide dismutase (SOD) activity, and diminished serum CK and AST activities, compared to the I/R group.