Objectives: Sympathetic drive, especially to the heart, is elevated in heart failure and is strongly associated with poor outcome. The mechanisms causing the increased sympathetic drive to the heart remain poorly understood. Catheter-based renal denervation (RDN),which reduces blood pressure (BP) and sympathetic drive in hypertensive patients, is a potential treatment in heart failure. The aim of this study was to investigate the short-term effects of catheter-based RDN on BP, heart rate (HR) and cardiac sympathetic nerve activity (CSNA) and on baroreflex function in a conscious, large animal model of heart failure. Methods: Adult Merino ewes were paced into heart failure (ejection fraction b 40%) and then instrumented to directly record CSNA. The resting levels and baroreflex control of CSNA and HR were measured before and 24 h after bilateral renal (n = 6) or sham (n = 6) denervation. RDN was performed using the Symplicity Flex Catheter System® (Medtronic) using the same algorithm as in patients. Results: Catheter-based RDNsignificantly reduced resting diastolic BP (P b 0.01) and mean arterial blood pressure (P b 0.05), but did not change resting HR or CSNA comparedwith sham denervation. Renal denervation reduced the BP at which CSNA was at 50% of maximum (BP50; P b 0.005) compared with sham denervation. Conclusions: In an ovine model of heart failure, catheter-based RDN did not reduce resting CSNA in the shortterm. There was, however, a lack of a reflex increase in CSNA in response to the fall in arterial pressure due to a leftward shift in the baroreflex control of CSNA, which may be due to denervation of renal efferent and/or afferent nerves.