Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Rationale: Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in heart failure (HF) and can contribute to arrhythmias induced by b-Adrenergic receptor-mediated sarcoplasmic reticulum calcium leak. Objective: To evaluate the effect of CaMKII inhibition on ventricular tachycardia (VT) induction in conscious HF and naive rabbits. Methods and Results: Nonischemic HF was induced by aortic insufficiency and constriction. Electrocardiograms were recorded in rabbits pretreated with vehicle (saline) or the CaMKII inhibitor KN-93 (300 mg/kg); VT was induced by infusion of increasing doses of norepinephrine (1.56-25 mgkg21min21) in naive (n = 8) and HF (n = 7) rabbits. With saline, median VT dose threshold in HF was 6.25 versus 12.5 mgkg21min21 norepinephrine in naive rabbits (P = 0.06). Pretreatment with KN-93 significantly increased VT threshold in HF and naive rabbits (median = 25 mgkg21min21, P , 0.05 vs. saline for both groups). Mean cycle length of VT initiation was shorter in HF (221 6 20 milliseconds) than naive (296 6 23 milliseconds, P , 0.05) rabbits with saline; this difference was not significant after treatment with KN-93. Conclusions: KN-93 significantly reduced arrhythmia inducibility and slowed initiation of VT, suggesting that CaMKII inhibition may have antiarrhythmic effects in the failing human heart.