Telmisartan is an angiotensin II receptor blocker and partial peroxisome proliferator-activated receptor gamma agonist that modulates the renin-angiotensin-aldosterone system. It is used primarily to manage hypertension, diabetic nephropathy, and congestive heart failure. Recent studies have reported that myocardial infarction (MI) has occurred in telmisartan-treated patients.The purpose of the study was to investigate the specific conditions and underlying mechanisms that may result in telmisartan-induced MI. We evaluated the effect of telmisartan on whole hearts, cardiomyocytes, and cardiac sarcolemmal ion channels. Hearts of 8-week-old male Sprague-Dawley rats were perfused with 3, 10, 30, or 100 μM telmisartan or losartan, or normal Tyrode’s solution (control) for 3 hours. We found that telmisartan induced myocardial infarction, with an infarct size of 21% of the total at 30 μM (P<0.0001) and 63% of the total area at 100 μM (P<0.001). Telmisartan also induced cardiac dysfunction (e.g., decreased heart rate, diminished coronary flow, hypercontracture, and arrhythmia). Confocal microscopy demonstrated that 30 μM telmisartan significantly elevated intracellular Ca2+ level leading to hypercontracture and cell death. Patch clamp analysis of isolated cardiomyocytes revealed that telmisartan induced Na+ overload by slowing the inactivation of voltage-gated Na+ current (INa), activating the reverse-mode of Na+-Ca2+ exchanger activity, and causing Ca2+ overload. Telmisartan significantly delayed inactivation of the voltage-gated Na+ channel causing cytosolic Na+ overload, prolonged action potential duration, and subsequent Ca2+ overload. Above 30 μM, telmisartan may potentially cause cardiac cell death and MI.