Abstract Background Renal sympathetic denervation (RDN) is one of the invasive treatment options for the patients with hypertension (HTN) who are resistant to antihypertensive therapy (AHT). The short-term efficacy of RDN has been proven in a number of randomized clinical trials, but remains controversial, the data on its long-term efficacy are limited. Purpose To evaluate the natural course of HTN, to assess long-term major adverse cardiovascular events (MACEs) and other clinically significant outcomes, as well as AHT efficacy and its features in patients with truly resistant HTN after bilateral RDN during extended prospective follow-up. Methods We included 22 patients with truly resistant HTN (median 57 y.o., 9 males), in whom RDN was performed during 2012–2015 in the clinical center of excellence. We assessed initial and further (after 1 year and after ≥5 years) office and 24-hour BP values, as well as AHT history in detail. Long-term MACEs and other cancer-related outcomes were recorded. The baseline quality of life (QoL) and its dynamics were assessed with the use of EQ-5D-5L questionnaire at all timepoints. Multiple linear regression was used to find possible predictors of the efficacy of RDN. Results The median follow-up after the RDN was 6 (from 5 to 8) years. A significant decrease in office and 24-hour systolic (S) and diastolic BPs was observed at 12 months after RDN compared to initial values (Δ −24 and −12 mm Hg, p<0.005; Δ −10 and −7 mm Hg, p<0.05, respectively). There were 7 patients with office SBP on-target (<140 mm Hg), and 12 patients were considered responders (SBP decrease more than 10 mm Hg from the baseline). These numbers increased to 10 and 14 patients after 6 years after RDN, respectively. A causal relationship between changes in office SBP was found only for SBP baseline values (β −0.6, p=0.02). No differences in the number of medications were noted during follow-up (4.4 versus 4.1 versus 4.1 drugs, p=0.41). We have recorded 10 MACEs and 5 cancer cases with various types with no fatal outcomes. The QoL significantly improved at 12 months after RDN (+9.7 points, p=0.01), however a negative trend was observed in the next 6 years (−13,8 points, p=0,02) with return to the reference. No association was observed between BP and QoL changes in two timepoints (p=0,65). Conclusions The RDN shows a pronounced clinical effect in patients with resistant HTN up to 6 years, and is not accompanied by an AHT intensification, and also is not associated with QoL changes. The initial positive trend for QoL completely harked back after 5 years which may be associated with the development of MACEs. The only predictor of RDN positive effect seems to be baseline office SBP levels. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Russian Science Foundation Study flow-chartChanges in BPs during follow-up