Background Heart failure (HF) is associated with chronic sympathetic activation. Renal denervation (RDN) aims to reduce sympathetic activity by ablating the renal sympathetic nerves. We investigated the effect of RDN in patients with chronic HF and concurrent renal dysfunction in a prospective, multicenter, single-arm feasibility study. Methods and Results Thirty-nine patients with chronic systolic HF (left ventricular ejection fraction [LVEF] <40%, New York Heart Association class II-III,) and renal impairment (estimated glomerular filtration rate [eGFR; assessed with the use of the Modification of Diet in Renal Disease equation] < 75 mL • min−1 • 1.73 m−2) on stable medical therapy were enrolled. Mean age was 65 ± 11 years; 62% had ischemic HF. The average number of ablations per patient was 13 ± 3. No protocol-defined safety events were associated with the procedure. One subject experienced a renal artery occlusion that was possibly related to the denervation procedure. Statistically significant reductions in N-terminal pro–B-type natriuretic peptide (NT-proBNP; 1530 ± 1228 vs 1428 ± 1844 ng/mL; P =.006) and 120-minute glucose tolerance test (11.2 ± 5.1 vs 9.9 ± 3.6; P =.026) were seen at 12 months, but there was no significant change in LVEF (28 ± 9% vs 29 ± 11%; P =.536), 6-minute walk test (384 ± 96 vs 391 ± 97 m; P =.584), or eGFR (52.6 ± 15.3 vs 52.3 ± 18.5 mL • min−1 • 1.73 m−2; P =.700). Conclusions RDN was associated with reductions in NT-proBNP and 120-minute glucose tolerance test in HF patients 12 months after RDN treatment. There was no deterioration in other indices of cardiac and renal function in this small feasibility study.