Introduction: The transient receptor potential 1 channel (TRPV1) mediates signals from pain, heat, and/or noxious stimuli. TRPV1 sensitization can occur via a protein kinase C (PKC)-dependent mechanism in neurons. Therefore, we tested whether TRPV1 is a mediator of cardioprotection in models of ischemia-reperfusion and whether the molecular mechanism of cardioprotection occurs via PKC-induced TRPV1 channel sensitization. Methods: Male Sprague Dawley rats and H9C2 left ventricle-derived cells were used for whole animal and cellular ischemia-reperfusion studies to test this hypothesis. Statistical analysis regarding infarct size, calculated as percentage of area at risk per left ventricle, was performed by a one way ANOVA (*P<0.01). Results: Remote preconditioning-induced infarct size reduction via an abdominal surgical incision was blocked by prior administration of a selective TRPV1 peptide inhibitor, V1-B (3.0mg/kg), given over the incision site (Incision: 44±2*% V1-B+Incision: 65±2% versus Control: 64±1% n=6/group). Capsaicin (0.3mg/kg) given intravenously through the internal jugular vein reduced infarct size in vivo , which was blocked by prior capsazepine (TRPV1 inhibitor, 3.0mg/kg) administration (Capsaicin: 43±2* Capsaicin+ capsazepine: 64±4 versus Control: 62±3, n=7/group). Further in an ex vivo isolated heart model, infarct size reduction afforded by the selective epsilon PKC activator (pseudo epsilon RACK, 1uM) was partially blocked with prior treatment of V1-B (1uM), the TRPV1 peptide blocker (pseudo epsilon RACK: 20±2*%, pseudo epsilon RACK+V1-B: 42±4% versus control: 47±4%, n=7/group). TRPV1 expression was found in both whole heart homogenate and in the H9C2 cell line. Using a model of ischemia-reoxygenation in H9C2 cells, capsaicin treatment before and during ischemia-reoxygenation reduced cellular damage as assessed by MTT and LDH assays. Greater damage occurred with TRPV1 inhibition by capsazepine compared to control. Conclusions: Our studies suggest TRPV1 contributes an essential role for both remote and direct cardioprotection. Further studies are ongoing to determine the post-translational sites on TRPV1 and how a TRPV1-epsilon PKC protein-protein interaction induces cardioprotection.