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The effectiveness of renal sympathetic denervation (RDN) as a treatment for therapy-resistant hypertension has been doubted as the Simplicity-HTN-3 trial was unable to show any treatment benefit over sham procedure. This might partly be explained by a high procedural variability in treatment with radiofrequency-based catheters. Recently, newer systems for RDN, like ultrasound-based devices, have been introduced into practice. To date however, data on their effectiveness for the treatment of resistant hypertension are scarce. We sought to evaluate the safety and effectiveness of an ultrasound-based, balloon-irrigated RDN catheter in a larger single-center cohort.Patients with therapy-resistant hypertension [average blood pressure (BP) >135 mmHg SBP or >90 mmHg DBP in ambulatory BP measurement despite at least three antihypertensive drugs, including at least one diuretic] underwent ultrasound-based RDN. Treatment effect was assessed by comparing BP values at baseline and 3 months after the procedure. Patients underwent renal artery duplex sonography or MRI before and after RDN to exclude renal artery stenosis.Fifty consecutive patients underwent ultrasound-based RDN, of which 25 had undergone an unsuccessful radiofrequency RDN before. Mean SBP change at 3 months was −9.7 ± 12.6/−10.6 ± 13.7/−8.2 ± 15.2 mmHg (ambulatory 24-h mean/daytime/night, P < 0.001 for all) and DBP changed by −5.1 ± 7.4/−5.8 ± 7.8/−3.9 ± 10.3 mmHg (P ≤ 0.001/<0.001/0.01). No new renal artery stenosis could be detected after RDN.Ultrasound-based RDN seems to be well tolerated and effective for the treatment of patients with therapy-resistant hypertension.