Background: Curcumin, a polyphenolic compound derived from turmeric, has protective effects on myocardial injury through attenuation of oxidative stress and inflammation. Toll-like receptor 2 (TLR2), a key mediator of the innate immune system, is involved in myocardial infarction (MI) and examined if controlled by curcumin. Methods: Rat cardiomyocytes (CMs) were stimulated with tumor necrosis factor (TNF)-慣, peptidoglycan (PGN, a TLR2 agonist) or hypoxia/reoxygenation (H/R) with or without curcumin pretreatment. Sprague-Dawley rats were fed curcumin (300 mg/kg/day) one week before cardiac ischemia/reperfusion (I/R) injury. Results: Both levels of mRNA and protein of TLR2 were upregulated in infarcted myocardium, while TLR4 remained unchanged. In CMs, TLR2 and monocyte chemoattractant protein (MCP)-1 mRNA were increased by TNF-慣, PGN, or H/R, whereas blunted by curcumin. Immunofluorescence staining of CMs also showed that TLR2 and MCP-1 were increased after H/R, whereas curcumin pretreated CMs were not. In animal study, two weeks after I/R TLR2 were increased in infarct zone, whereas stayed unchanged in Cur+I/R group. Cardiac fibrosis was measured over times and it showed a significant decrease at 1 week after I/R injury in Cur+I/R group in compared with that in I/R group. Macrophage infiltration and high-mobility group box 1 (HMGB1, an endogenous TLR2 agonist) expression were increased in I/R group, whereas decreased in Cur+I/R group. The deteriorations of left ventricular end diastolic dimension (LVEDd), fractional shortening (FS), and ejection fraction (EF) were significantly attenuated at day 3 and preserved until day 14 in Cur+I/R group. Cardiac contractility was also improved (max dP/dt in Cur+I/R group; 9660짹612 vs. in I/R group; 8119짹366, p<0.05). Conclusion: These results suggest that selective inhibition of TLR2 by curcumin could be preventive and therapeutic for myocardial infarction.