Abstract Background Heart Failure (HF) is increasing in prevalence and is a major cause of morbidity and mortality, despite advances in medical and device therapy. Autonomic imbalance, with excess sympathetic activation and decreased vagal tone, is an integral component of the pathophysiology of HF. Objectives INOVATE-HF was designed to assess the safety and efficacy of vagal nerve stimulation (VNS) among patients with heart failure and a reduced ejection fraction. Methods INOVATE-HF was a multinational, randomized trial involving 85 centers in patients with chronic HF, NYHA III symptoms and ejection fraction < 40%. Patients were assigned to device implantation to provide VNS (Active) or continued medical therapy (Control) in a 3:2 ratio. The primary efficacy endpoint was the composite of death from any cause or first event for worsening HF. Results There were 707 patients randomized and followed for a mean of 16 months. The primary efficacy outcome occurred in 132 of 436 patients in the VNS group, as compared with 70 of 271 in the control group (30.3% vs. 25.8%; hazard ratio, 1.14; 95% confidence interval CI, 0.86 to 1.53; P = 0.37). During the trial, the estimated annual mortality rates of 9.3% and 7.1%, respectively (p=0.19). Quality of life, New York Heart Association Class and 6 minute walking distance were favorably affected by VNS (p’s < 0.05), but left ventricular end-systolic volume index was not different (P=0.49). Conclusions VNS does not reduce the rate of death or HF events in chronic HF patients. (Clinical Trials.gov number NCT01303718)