Baroreflex activation therapy (BAT) produces a central inhibition of cardiac sympathetic outflow and, concomitantly, an increased cardiac vagal activity via a physiological reflex pathway. In a pilot study in 11 patients with NYHA class III heart failure (HF), BAT produced a persistent significant reduction of muscle sympathetic nerve activity over a 21-month follow-up and a dramatic decrease in the number and length of hospitalizations. In a multinational, prospective, randomized, parallel-controlled, clinical trial in 146 NYHA functional class III HF, BAT produced a significant N-terminal pro-brain natriuretic peptide reduction (p = 0.02). This was associated with a trend toward few in hospital days for HF. BAT might become a powerful tool to manipulate autonomic alterations of HF at their origin and thus profoundly affect advanced HF patient prognosis.