Gain-of-function mutations in RyR2 are known to cause lethal arrhythmias such as catecholaminergic ventricular tachycardia (CPVT). In CPVT, reduction of RyR2 activity is thought to suppress arrhythmias, but there are no clinically available antiarrhythmic drugs with RyR2-specific inhibitory action. We developed a high-affinity (IC50 of ~15nM) and selective RyR2 inhibitor, TMDJ-035, based on a hit compound identified in a high-throughput screening. TMDJ-035 effectively suppressed arrhythmias in CPVT mouse models harboring mutant RyR2s. Unlike conventional anti-arrhythmic drugs, i.e., Na channel inhibitors, Ca channel inhibitors, ß-blockers, TMDJ-035 did not affect ECG parameters or cardiac contractile function at the effective doses. Our results demonstrate that the specific suppression of RyR2 activity is highly effective in preventing and treating arrhythmias caused by RyR2 hyperactivation.