Background: Renal denervation (RDN) with radiofrequency ablation substantially reduces blood pressure in patients with treatment-resistant hypertension. We assessed the long-term antihypertensive effects and safety. Methods: Symplicity HTN-1 is an open-label study that enrolled 153 patients, of whom 111 consented to follow-up for 36 months. Eligible patients had a systolic blood pressure of at least 160 mm Hg and were taking at least three antihypertensive drugs, including a diuretic, at the optimum doses. Changes in office systolic blood pressure and safety were assessed every 6 months and reported every 12 months. This study is registered with ClinicalTrials.gov, numbers NCT00483808, NCT00664638, and NCT00753285. Findings: 88 patients had complete data at 36 months. At baseline the mean age was 57 (SD 11) years, 37 (42 ) patients were women, 25 (28 ) had type 2 diabetes mellitus, the mean estimated glomerular filtration rate was 85 (SD 19) mL/min per 1?73 m2, and mean blood pressure was 175/98 (SD 16/14) mm Hg. At 36 months significant changes were seen in systolic (-32?0 mm Hg, 95 CI -35?7 to -28?2) and diastolic blood pressure (-14?4 mm Hg, -16?9 to -11?9). Drops of 10 mm Hg or more in systolic blood pressure were seen in 69 of patients at 1 month, 81 at 6 months, 85 at 12 months, 83 at 24 months, and 93 at 36 months. One new renal artery stenosis requiring stenting and three deaths unrelated to RDN occurred during follow-up. Interpretation: Changes in blood pressure after RDN persist long term in patients with treatment-resistant hypertension, with good safety.