Aim: The aim of this studywas to determine long-term results of renal artery denervation for treatment of treatment-resistant hypertension in the SYMPLICITY HTN-2 study. Methods: SYMPLICITY HTN-2 randomized 106 subjects with treatment-resistant hypertension to renal denervation or medical therapy alone. At 6 months, 37 control subjects crossed over to renal denervation. Office blood pressure measurements, antihypertensive medication use, and safety events were followed every 6 months through 3 years. Results: Follow-up was available at 36 months in 40 of 52 subjects in the initial renal denervation group and at 30 months in 30 of 37 subjects who crossed over and received renal denervation at 6 months. Baseline blood pressure was 184±19/99±16 mmHg in all treated subjects. At 30-month post-procedure, systolic blood pressure decreased 34 mmHg (95% CI: -40, -27, P<0.01) and diastolic blood pressure decreased 13 mmHg (95% CI: -16, -10, P<0.01). The systolic and diastolic blood pressure reduction at 36 months for the initial renal denervation group was -33 mmHg (95% CI: -40, -25, P<0.01) and -14 mmHg (95% CI: -17, -10, P<0.01), respectively. Procedural complications included one haematoma, and one renal artery dissection before energy delivery thatwas treated successfully. Later complications included two cases of acute renal failure, which fully resolved, 15 hypertensive events requiring hospitalization, and three deaths. Conclusion: Renal denervation resulted in sustained lowering of blood pressure at 3 years in a selected population of subjects with severe, treatment-resistant hypertension without serious safety concerns.