Background Inflammation is one of important mechanisms for myocardial ischemia reperfusion injury (IRI). Ischemia postconditioning (IPOC) can protect the heart against IRI by inhibiting inflammation, but its cardioprotection is weaker than that of ischemia preconditioning. Recently, the alpha 7 subunit-containing nicotinic acetylcholine receptor (alpha 7nAChR) agonist has shown anti-inflammatory effects in many diseases related to inflammation. This randomized controlled experiment was designed to evaluate whether combined postconditioning with IPOC and the alpha 7nAChR agonist could produce an enhanced cardioprotection in a rat in vivo model of acute myocardial IRI. Methods Fifty Sprague-Dawley rats were randomly divided into five equal groups: sham group, control group, IPOC group, alpha 7nAChR agonist postconditioning group (APOC group) and combined postconditioning with IPOC and alpha 7nAChR agonist group (combined group). Hemodynamic parameters were recorded during the periods of ischemia and reperfusion. Serum concentrations of troponin I (TnI), tumor necrosis factor alpha (TNF-alpha) and high-mobility group box 1 (HMGB-1) at 180 minutes after reperfusion were assayed in all groups. At the end of the experiment, the infarct size was assessed from excised hearts by Evans blue and triphenyl tetrazolium chloride staining. Results As compared to the sham group, the infarct size in the other four groups was significantly increased, serum levels of TnI, TNF-alpha and HMGB1 in the control group and TNF-alpha, HMGB1 in the IPOC group were significantly increased. The infarct size and serum concentrations of TNF-alpha, HMGB1 and TnI in the IPOC, APOC and combined groups were significantly lower than those in the control group. As compared to the IPOC group, the infarct size in the combined group was significantly decreased, serum concentrations of TnI, TNF-alpha and HMGB1 in the APOC and combined groups were significantly reduced. Although the infarct size was significantly smaller in the combined group than in the APOC group, serum levels of TNF-alpha and HMGB1 were significantly higher in the combined group than in the APOC group. Conclusions In a rat in vivo model of acute myocardial IRI, combined postconditioning with IPOC and the alpha 7nAChR agonist can produce enhanced protection against myocardial IRI by increasing the anti-inflammatory effect. Chin Med J2012;125(2):326-331