A growing number of clinical studies suggest that in heart failure renal denervation (RDN) has beneficial effects on the autonomic control of the heart. There is also experimental evidence that surgical RDN improves sodium handling and clearance in heart failure. The aim of this study was to determine the effects of catheter-based RDN on the sympathetic and parasympathetic control of the heart, and salt and water handling capacity of the kidneys, in sheep with established heart failure. A randomized, controlled study was conducted in 10 sheep with heart failure (ejection fraction<40%) induced by rapid ventricular pacing. Sheep underwent either bilateral RDN using the Symplicity denervation system or sham denervation and were studied 1 and 6 weeks after RDN. In established ovine heart failure, at 6 weeks after catheter-based RDN, heart rate significantly decreased, estimates of resting and maximal parasympathetic control of heart rate increased, and cardiac sympathetic nerve activity decreased. Compared with sham denervation, there was an increase in the resting sodium and water excretion 6 weeks after catheter-RDN and an improved ability of the kidneys to excrete a nonhypertensive saline load. After catheter-based RDN, renal norepinephrine levels were reduced by 70% compared with sham denervation. In established heart failure, RDN induced a beneficial shift in both arms of the autonomic nervous control of the heart and improved the ability of the kidneys to excrete sodium and water. Thus, effective catheter-based RDN may be beneficial to both the heart and kidneys in heart failure.