Objective: Although it is believed that sodium-driven acid–base transport plays a central role in the development of the reperfusion injury that follows cardiac ischemia, research to date has demonstrated only a role for Na⁺/H⁺ exchange (NHE). However, Na⁺-driven HCO^–₃ transport, which is quantitatively as important as NHE in cardiac cells, has not been examined. Methods and Results: Here the results show that a neutralizing antibody raised against the human heart electrogenic Na⁺/HCO₃⁻ cotransporter (hhNBC) blocked the recovery of pH after acidic pulse both in HEK-293 cells expressing hhNBC and in rat cardiac myocytes demonstrating the presence of an electrogenic NBC in rat cardiac myocytes similar to hhNBC. Administration of anti-NBC antibody to ischemic-reperfused rat hearts markedly protects systolic and diastolic functions of the heart during reperfusion. Furthermore, using a quantitative real-time RT-PCR (TaqMan) and Western blot analysis we demonstrated that in human cardiomyopathic hearts, mRNA and protein levels of hhNBC increase, whereas mRNA levels of the electroneutral Na⁺/HCO₃⁻ cotransporter (NBCn1) remain unchanged. Conclusion: Our data provide evidence that inhibition of hhNBC, whose role in cardiac pathologies could be amplified by overexpression, represents a novel therapeutic approach for ischemic heart disease.