Abstract: Background: Recently it has been noted that Cyclooxygenase-2 (COX-2) is involved in early phase of ischemic preconditioning (IPC) induced cardioprotection. The present study was designed to investigate the role of COX-2 in the cardioprotective effect of remote aortic preconditioning (RAPC) in rat. RAPC was given by 4 times of 5’ occlusion of abdominal aorta. Materials and Methods: Isolated perfused rat heart was subjected to global ischemia of 30 min., followed by reperfusion for 120 min. Coronary effluent was analyzed for LDH and CK release to access the degree of cardiac injury. Myocardial infarct size was estimated macroscopically using TTC staining. Results: RAPC produced a significant decrease in LDH and CK release and decrease in the myocardial infarct size, as compared to ischemia/reperfusion (I/R) control group. Pretreatment with celecoxib, a selective COX-2 inhibitor and glibenclamide, a blocker of KATP channels, given separately significantly attenuated the RAPC-induced cardioprotection. The cardioprotective effect of celecoxib and glibenclamide, administered in combination was almost equal to the sum total of the effect produced by these drugs when administered singly. Conclusion: On the basis of these results it was concluded that the cardioprotective effect of RAPC may be mediated through upregulation of COX-2 and subsequent activation of KATP channels.