Background: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment. Methods: Patients with a daytime ambulatory BP ≥135/85 mm Hg and <170/105 mm Hg after a 4-week discontinuation of up to 2 antihypertensive medications, and a suitable renal artery anatomy, were randomized to RDN (n=74) or sham (n=72). Patients were to remain off antihypertensive medications throughout the first 2 months of follow-up unless safety BP criteria were exceeded. Between 2 and 5 months, if monthly measured home BP was ≥135/85 mm Hg, a standardized stepped-care antihypertensive treatment was recommended consisting of the sequential addition of amlodipine (5 mg/d), a standard dose of an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and hydrochlorothiazide (12.5 mg/d), followed by the sequential uptitration of hydrochlorothiazide (25 mg/d) and amlodipine (10 mg/d). Outcomes included the 6-month (1) change in daytime ambulatory systolic BP adjusted for medications and baseline systolic BP, (2) medication burden, and (3) safety. Results: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group (P=0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P=0.010 and 1.4±1.5 versus 2.0±1.8, P=0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (-18.1±12.2 versus -15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: -4.3 mm Hg, 95% confidence interval, -7.9 to -0.6, P=0.024). There were no major adverse events in either group through 6 months. Conclusions: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02649426.