Background: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. Methods: In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20–80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. Findings: Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure −7·0 mm Hg, 95% CI −12·0 to −2·1; p=0·0059, 24 h diastolic blood pressure −4·3 mm Hg, −7·8 to −0·8; p=0.0174, office systolic blood pressure −6·6 mm Hg, −12·4 to −0·9; p=0·0250, and office diastolic blood pressure −4·2 mm Hg, −7·7 to −0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference −6·8 mm Hg, 95% CI −12·5 to −1·1; p=0·0205), 24 h systolic blood pressure (difference −7·4 mm Hg, −12·5 to −2·3; p=0·0051), office diastolic blood pressure (difference −3·5 mm Hg, −7·0 to −0·0; p=0·0478), and 24 h diastolic blood pressure (difference −4·1 mm Hg, −7·8 to −0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. Interpretation: Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. Funding: Medtronic.