Background Long term safety and efficacy data of multi-electrode ablation system for renal denervation (RDN) in patients with drug resistant hypertension (dRHT) are limited. Methods and results We studied 46 patients (age: 60 ± 10 years, 4.7 ± 1.0 antihypertensive drugs) with drug resistant hypertension (dRHT). Reduction in office BP at 24 months from baseline was - 29/- 13 mm Hg, while the reduction in 24-hour ambulatory BP and in home BP at 24 months were - 13/- 7 mm Hg and - 11/- 6 mm Hg respectively (p < 0.05 for all). A correlation analysis revealed that baseline office and ambulatory BP were related to the extent of office and ambulatory BP drop. Apart from higher body mass index (33.3 ± 4.7 vs 29.5 ± 6.2 kg/m2, p < 0.05), there were no differences in patients that were RDN responders defined as ≥ 10 mm Hg decrease (74%, n = 34) compared to non-responders. Stepwise logistic regression analysis revealed no prognosticators of RDN response (p = NS for all). At 24 months there were no new serious device or procedure related adverse events. Conclusions The EnligHTN I study shows that the multi-electrode ablation system provides a safe method of RDN in dRHT accompanied by a clinically relevant and sustained BP reduction.