BACKGROUND The effects of hydroxyethyl starch 130/0.4 (HES130/0.4) on myocardial ischemia/reperfusion (I/R) injury and its mechanism are uncertain. The aim of this study was to investigate the protective effects of HES 130/0.4 on myocardial I/R injury. METHODS Forty-eight Sprague-Dawley rats were assigned to sham-operation group (S group), ischemia-reperfusion group (I/R group), albumin-I/R group (A-I/R group) and HES130/0.4-I/R group (H-I/R group). The fluids were administered at 25 minutes after ischemia. H-I/R group was given 7.5 ml/kg of HES 130/0.4; I/R group and A-I/R group received the same volume of normal saline and 5% albumin, respectively. The rats in S group were sham operated and received the same fluid as I/R group. After 30 minutes of ischemia and 3 hours of reperfusion, blood samples were taken for cytokines assay, myocardium was excised for detection of NF-κB activity and myocardial infarction areas were taken for immunohistochemical analysis. RESULTS Hemodynamic parameters of H-I/R group were better than I/R and A-I/R groups at all designated time points. The results of 2,3,5-triphenyl-tetrazolium (TTC) and HE staining were better in the H-I/R group. Myeloperoxidase (MPO), NF-κB activity and concentrations of TNF-α, IL-1β were elevated markedly in I/R groups. HES130/0.4 lessened the release of TNF-α and IL-1β consistent with the reduction of MPO activity, and HES 130/0.4 inhibited the activity of NF-κB in H-I/R group. The number of apoptotic cells in the H-I/R group was also significantly reduced compared with I/R and A-I/R group CONCLUSIONS HES130/0.4 has a protective effect on I/R injured myocardium, probably by inhibiting NF-κB activity, reducing the release of pro-inflammatory cytokines and interfering with the apoptosis of cardiomyocytes.