The current study investigated the role of sRAGE in the production of IFN- in macrophages with I/R treatment. The number of macrophages in myocardial tissues treated with I/R with or without sRAGE was determined via immunohistochemical staining. Proliferative activity of macrophages was analyzed by a 5-BrdU incorporation assay. Differentiation of macrophages was detected via immunofluorescence staining of iNOS (M1 macrophage marker). IFN- production, due to sRAGE stimulation, in Raw 264.7 macrophages and the NF-B signaling pathway were measured using western blotting. A ChIP assay was used to examine the interactions between NF-B and the promoter of IFN-. The results showed that the number of macrophages in I/R-treated myocardial tissues was increased following sRAGE infusion. Proliferation of macrophages was increased significantly in the presence of sRAGE; after I/R treatment, the cells preferred to differentiate into M1 macrophages. IFN- expression in Raw 264.7 macrophages was suppressed by an NF-B inhibitor (Bay117082) but enhanced by sRAGE, with or without I/R treatment. Furthermore, sRAGE increased the phosphorylation of IB, IKK and NF-B, as well as the translocation of NF-B into the nucleus of Raw 264.7 macrophages, with or without I/R treatment. ChIP results showed that sRAGE promoted NF-B binding to the promoter of IFN- in Raw 264.7 macrophages. Therefore, the findings of the present study indicated that sRAGE protected the heart from I/R injuries, which might be mediated by promoting infiltration and the differentiation of macrophages into M1, which would then synthesize and secrete IFN- through activating the NF-B signaling pathway.