BACKGROUND: The level of sympathetic nervous activity is a major determinant of prognosis in patients with heart failure. OBJECTIVE: The purpose of this investigation was to perform a proof-of-principle trial of therapeutic endoscopic left thoracic sympathetic blockade in heart failure patients to assess safety and immediate effects. METHODS: Fifteen patients with dilated cardiomyopathy and left ventricular ejection fraction (LVEF) < 40%, New York Heart Association functional class II or III, and heart rate > 65 bpm, despite either adequate betablocker use or intolerant to it, were enrolled. Ten patients underwent left infra-stellate ganglion plus T3-T4 interspinal space clipping through videothoracoscopy, while the other five patients were randomized to a control group. RESULTS: None of the treated patients had any procedure-related adverse cardiovascular events at the perioperative period. Two patients from the surgical group died due to pulmonary thromboembolism or myocardial infarction within 6 months of the initial follow-up, while three patients from the control group had heart failure progression and died or developed cardiogenic shock during the same period. Treated patients presented improvement in quality of life, level of physical activity and LVEF (from 25 ± 9% to 32 ± 8%, p=0.024) at 6 months of follow-up, whereas these parameters did not change in control patients. CONCLUSION: Endoscopic left thoracic sympathetic blockade is feasible and appears to be safe in severe heart failure patients. This initial study suggests that this procedure might be an effective alternative approach to sympathetic blockade in the treatment of dilated cardiomyopathies.