Exenatide and cyclosporine A have been shown to moderately protect against myocardial reperfusion injury leading to reduction of infarct size in patients. Our objective was to investigate whether the combined treatment with exenatide (glucagon-like peptide 1 receptor agonist) and cyclosporine A or parstatin 1-26 (inhibitors of mitochondrial permeability transition pore and/or inflammation) is more beneficial than either agent alone. Rabbits underwent 40 minutes of ischemia and 120 minutes of reperfusion. Intravenous bolus administration of exenatide or cyclosporine A, 10 minutes before reperfusion, reduced infarct size by 38% (P < 0.05) and 40% (P < 0.05), and cardiac troponin I (cTnI) plasma levels by 48% (P < 0.05) and 36% (P < 0.05), respectively, compared with control. The combined administration of both agents resulted in an additive decrease of infarct size by 55% (P < 0.05) and cTnI release by 61% (P < 0.05). Also, combined treatment of exenatide and parstatin 1-26 enhanced infarct size reduction (62%, P < 0.05), compared with monotherapies (41% for parstatin 1-26, P < 0.05; 43% for exenatide, P < 0.05). In contrast, the combined administration of parstatin 1-26 and cyclosporine A canceled out the cardioprotective effects observed by monotherapies. These results suggest that, for the therapy of myocardial reperfusion injury the combined administration of exenatide and cyclosporine A or parstatin 1-26 is more effective than monotherapies and may provide advantageous clinical outcome.