Cardiac innate immunity plays a central role in defense response and homeostasis in the heart. Previously, we reported that T. cruzi infection, the ethiological agent of chagasic cardiomyopathy, protects isolated cardiomyocytes from apoptosis. Our objective was to elucidate cardiomyocyte innate immune response to T. cruzi infection and its possible role in the cytoprotection. We found that TLR2 expression, but not TLR4, was strongly increased by the parasite in BALB/c neonatal cardiomyocyte cultures (CMC). The transfection of CMC with a dominant-negative TLR2 plasmid blocked the parasite-induced cytoprotective effect, 48h after serum starvation. Among the cytokines tested (IL6, TNFá, IL1b, IL17, IL10 and IL4), we could detect a rapid, sustained and NF-kB-dependent production of IL6. Moreover, infection induced IL6 production was blocked in infected cultures transfected with dnTLR2 (P<0.001). The treatment of CMC with IL6 neutralizing antibody abolished the parasite-induced cytoprotection (P<0.02). In addition, we found that IL6 produced by infected cardiomyocytes increased the p-STAT3 in CMC. In agreement with the results obtained in vitro, we observed an increased expression of TLR2 and BCL-2 in the cardiac fibers during the acute phase of the infection in vivo. Our results strongly suggest that the triggering of TLR2 signalling, followed by IL6 production and STAT3 activation, plays a key role in T. cruzi-elicited cardiomyocyte protection.