BACKGROUND: The SPYRAL HTN-ON MED (Global Clinical Study of Renal Denervation With the Symplicity Spyral Multielectrode Renal Denervation System in Patients With Uncontrolled Hypertension on Standard Medical Therapy) trial showed that radiofrequency renal denervation (RDN) using the Symplicity Spyral catheter yielded significant blood pressure (BP) reductions at 6 and 24 months compared with sham control in patients with hypertension on antihypertensive medications. In this prespecified analysis through the final follow-up, we evaluate the durability of BP reductions, antihypertensive medication use, and safety through 3 years. METHODS: SPYRAL HTN-ON MED is a global, randomized, sham-controlled trial enrolling patients with uncontrolled hypertension. Patients were prescribed 1 to 3 antihypertensive medications and randomized to RDN or a sham procedure. After 6 months, patients were unblinded, and sham patients could cross over to RDN. Crossover patients' values for BP and antihypertensive medications were imputed to 36 months using their last observation before crossover to RDN carried forward. Statistical analyses, including imputation, were exploratory and conducted on the intention-to-treat population. RESULTS: After 6 months, 74% of sham patients crossed over to undergo RDN. Patients undergoing RDN had statistically significant 24-hour ambulatory systolic BP reductions (treatment difference, -4.7 mm Hg; P=0.0028) and office systolic BP reductions (difference, -7.5 mm Hg; P=0.0002) compared with the sham control group through 36 months. At 36 months, the antihypertensive medication burden was balanced between groups (RDN, 5.2±5.0 versus 5.5±9.9; P=0.63). Crossover patients had significantly better office BP control after RDN. Clinical adverse events were rare. CONCLUSIONS: Compared with sham patients through 3 years, patients undergoing RDN had significantly greater 24-hour ambulatory and office BP reductions, with a similar medication burden. RDN maintained a durable safety profile through 3 years. REGISTRATION: URL: https://clinicaltrials.gov/study; Unique identifier: NCT02439775.