BACKGROUND-: Renal sympathetic nerve activation contributes to the pathogenesis of hypertension. Symplicity HTN-2, a multicenter, randomized trial, demonstrated that catheter-based renal denervation produced significant blood pressure lowering in treatment-resistant patients at 6 months after the procedure compared with control, medication-only patients. Longer-term follow-up, including 6-month crossover results, is now presented. METHODS AND RESULTS-: Eligible patients were on ≥3 antihypertensive drugs and had a baseline systolic blood pressure ≥160 mm Hg (≥150 mm Hg for type 2 diabetics). After the 6-month primary end point was met, renal denervation in control patients was permitted. One-year results on patients randomized to immediate renal denervation (n=47) and 6-month postprocedure results for crossover patients are presented. At 12 months after the procedure, the mean fall in office systolic blood pressure in the initial renal denervation group (-28.1 mm Hg; 95% confidence interval,-35.4 to-20.7; P<0.001) was similar to the 6-month fall (-31.7 mm Hg; 95% confidence interval,-38.3 to-25.0; P=0.16 versus 6-month change). The mean systolic blood pressure of the crossover group 6 months after the procedure was significantly lowered (from 190.0±19.6 to 166.3±24.7 mm Hg; change,-23.7±27.5; P<0.001). In the crossover group, there was 1 renal artery dissection during guide catheter insertion, before denervation, corrected by renal artery stenting, and 1 hypotensive episode, which resolved with medication adjustment. CONCLUSIONS-: Control patients who crossed over to renal denervation with the Symplicity system had a significant drop in blood pressure similar to that observed in patients receiving immediate denervation. Renal denervation provides safe and sustained reduction of blood pressure to 1 year. CLINICAL TRIAL REGISTRATION-: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00888433.