Abstract The mortality due to ischemic cardiovascular diseases is significantly higher in the elderly than in young adults. Myocardial ischemia-reperfusion (MI/R) can induce oxidative stress and an inflammatory response. We hypothesized that the increased vulnerability of the aged myocardium to reperfusion injury could be caused by a decreased anti-oxidative capacity rather than by an increased oxidant production following MI/R. Aged (20-months) and young (4-months) male F344 BN rats were subjected to 30 min of myocardial ischemia by ligating the left main coronary artery, followed by release of the ligature and 4 h of reperfusion. Four experimental groups, e.g., young rats with sham control operation; aged rats with sham control operation; young rats subjected to MI/R; and aged rats subjected to MI/R, were studied. Our results indicate that MI/R induced a significant (p<0.05) increase in infiltrated leukocytes (512 ± 66 cells/20 high power field, HPF) and myeloperoxidase (MPO) activity (39 ± 2.6 ng/g tissue) in the peri-necrotic areas of the hearts of young rats compared to aged MI/R rats (277 ± 32 cells/20 HPF of infiltrated leukocytes and 23 ± 1.8 ng/g tissue of MPO activity). These changes in the infiltrated leukocyte number and MPO activity were associated with an increase in superoxide generation in the peri-necrotic areas of the hearts of young rats (1524 ± 212 CPM/mg tissue) compared to aged rats (1166 ± 173 CPM/mg tissue). Moreover, plasma levels of tumor necrosis factor- (TNF- 311 ± 30.1 pg/ml) and interleukin-1 (IL-1 414 ± 27 pg/ml) in young MI/R rats were significantly (p<0.05) higher than those of aged MI/R rats (201 ± 19 pg/ml of TNF- and 287 ± 24 pg/ml of IL-1 ). However, plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and creatine kinase (CK) activity were increased at 223 ± 32 ng/ml and 356 ± 23 IU/L in aged MI/R rats compared to young MI/R rats (137 ± 15 ng/ml of 8-OHdG and 196 ± 14 IU/L of CK activities, respectively). The increased reperfusion damage observed in aged rats was associated with a significant decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in the plasma. Results of the present studies suggest that the enhanced ischemia-reperfusion injury in aged rat hearts following MI/R may be related to the reduced anti-oxidative capacity rather than to increased ROS production. These findings contribute to a better understanding of the effects of aging on oxidative stress and inflammatory responses of the heart following MI/R.