Objectives: Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). Aim of this study was to investigate whether postconditioning with the CpG-containing TLR9-ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Methods: Thirty min. LAD-occlusion was conducted in 12 weeks old C57BL/6 mice. Mice were treated with CpG i.p. 5 min. before reperfusion. Control group received PBS; sham group did not undergo ischemia. M-mode echocardiography (3, 7 and 28 days) and Millar® left ventricular (LV) catheter were performed (7 and 28 days) before hearts where excised and harvested for immunohistochemical (6, 24 hrs, 3, 7, 28 days), gene expression (6, 24 hrs, 3 days; Taqman® RT-qPCR), protein and FACS analysis (24 hrs, 3 days). Results: Mice treated with CpG showed significantly better LV function after 7- and 28-days reperfusion. Protein- and mRNA-expression of pro- and anti-inflammatory cytokines were significantly induced after CpG-treatment. Histology revealed fewer macrophages in CpG-mice after 24 hrs, confirmed by FACS-analysis with decrease in both, classically M1- and alternative M2a-monocytes. CpG-treatment reduced apoptosis and cardiomyocyte-loss and was associated with induction of adaptive mechanisms, e.g. of heme-oxigenase-1 and b-/a-MHC ratio. Pro-fibrotic markers col-Ia and -III induction was abrogated in CpG-mice, accompanied by fewer myofibroblasts. This lead to formation of a smaller scar. Differential MMP/TIMP-expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a TLR1 and -9 dependant manner. Conclusion: Our study suggests a cardioprotective mechanism of CpG-postconditioning, involving TLR-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV-function.