Objective: Therapy-resistant hypertension (RHTN) is associated with major adverse cardiovascular events. Increased sympathetic drive is considered to be one of mechanisms of resistance to antihypertensive treatment and associated with high blood pressure level. Sympathetic hyperactivity is also linked to increased blood pressure variability (BPV) resulting in worse prognosis. Renal denervation (RDN) reduces sympathetic activity and BP in some patients with RHTN, however data on the impact of the procedure on BPV are lacking. Aim of the present study was to assess effect of RDN on blood pressure levels and BPV during 2-years follow-up. Design and method: The study enrolled 22 consecutive patients (mean age 56 ± 10.2 years, 9 males) with confirmed true RHTN (mean of 4.2 ± 1.4 antihypertensive drugs intake) who underwent bilateral RDN procedure (Symplicity RDN System, Medtronic, USA). BP and BPV (by means of average real variability) were assessed by ABPM (BPLab, Petr Telegin, Russia) at baseline, 12-month and 24 month after procedure. Results: In overall population there was a decrease of both office and 24-hour SBP at 12 months after RDN (−26 ± 20.2 mmHg; −17.4 ± 10.8 mmHg; respectively, p < 0.05 for all), however further reduction at 24-month follow-up was only for “office” SBP (−22.8 ± 23 mmHg; p < 0.02 and −22.6 ± 17.6 mmHg; p = 0.3 respectively). 24-hour BPV decreased from 18.8 ± 4.4 mmHg to 17 ± 4.2 mmHg (−2.6 ± 3.7 mmHg, p < 0.0001) after 12 months and continued to decline to 15.36 ± 2.9 mmHg (−3.3 ± 2.5 mmHg, p < 0.001) two years after procedure. In 15 patients RDN provided decrease of BP level > 20 mm Hg, in 7 patients resulted in 10 mm Hg decrease. Both groups had a significant reduction of BPV in 24-month (−5.0 and −1.3 mmHg respectively;p < 0.001). There was a positive correlation between change of SBP, 24-h SBP and 24-h BPV at 24-month visit compared to baseline (r = 0.654 for office SBP/BPV; p = 0.02 and r = 0.628 for 24-h SBP/BPV; p = 0.02). Conclusions: RDN resulted in significant reduction of 24-BPV in patients with both marked and moderate decrease of blood pressure level indicating additional positive impact on adverse prognostic features of hypertension.