Background: Imbalance between the parasympathetic and sympathetic nervous systems is a recognized contributor to progression of chronic heart failure. Current therapy with beta adrenergic antagonists is designed to moderate the up-regulation of norepinephrine and sympathetic effects; however, to date, there are no therapies that specifically address the withdrawal of parasympathetic influences on cardiac function and structure. Methods/Results: In order to evaluate the impact of vagus nerve stimulation, an international multi-center randomized clinical trial (INOVATE-HF) has been designed to assess safety and efficacy of vagus nerve stimulation in symptomatic patients with heart failure on optimal medical therapy using the CardioFit System (BioControl Medical, Yehud, Israel). Up to 650 patients from 80 sites will be recruited and randomized in a 3:2 ratio to receive active treatment or standard optimal medical therapy. Inclusion criteria include left ventricular systolic dysfunction, the presence of New York Heart Association Class III symptoms, sinus rhythm, and QRS width less than 120 milliseconds. The study is powered to detect differences in the primary efficacy end point of all-cause mortality and heart failure hospitalization and 2 safety end points. Conclusion: Vagal nerve stimulation with CardioFit as a treatment for symptomatic heart failure is under active investigation as a novel approach to restore balance between the sympathetic and parasympathetic nervous systems. If shown to be safe and effective in decreasing heart failure events and mortality, this novel approach will impact the treatment paradigm for heart failure.