Background. Diabetic patients with resistant hypertension (RHT) are characterized by a high rate of annual decline in estimated glomerular filtration rate (eGFR) (up to 14 mL/min/1.73 m 2 ). The distal approach to sympathetic renal denervation (RD) reduces blood pressure (BP) to a greater extent compared with standard RD. However, the long-term effect of distal RD on the renal function remains unknown. Aim . The purpose of this study was to evaluate the long-term safety and nephroprotective efficacy profile of distal RD compared to conventional intervention in RHT patients with type 2 diabetes mellitus (T2DM) during a three-year follow-up. Material and Methods. Twenty seven patients (eight men) with true RHT and T2DM were included in a single-arm prospective interventional study (number NCT01499810 at ClinicalTrials.gov) (mean age of 61.6 ± 7.3 years; mean office (systolic/diastolic) BP of 171.8 ± 21.9/87.7 ± 17.7 mmHg; mean eGFR of 72.1 ± 19.9 mL/min/1.73 m²; and glycosylated hemoglobin level (HbA1c) of 6.3 ± 1.1%). Patients were randomized into two comparable groups of distant ( n = 13) and standard RD ( n = 14). Office BP, ABPM, renal Doppler ultrasound, renal function (eGFR (CKD-EPI) and 24-hour urinary albumin excretion (UAE)), and kidney MRI were assessed at baseline and annually during a three-year follow-up. Nineteen patients completed a 36-month follow-up (8 patients were treated by distal RD and 11 patients received the conventional procedure). Results. The change in eGFR during three-year follow-up was insignificant in group of distal RD (-5.3 ± 0.4 mL/min/1.73 m 2 , p = 0.63) and was comparable with the corresponding value in conventional RD group (–6.7 ± 4.2 mL/min/1.73 m 2 , p = 0.3), ( p = 0.7 for intergroup comparison) despite a more powerful decrease in 24-h systolic BP in the distal RD group relative to that in conventional RD group (–25.3 ± 15.3 vs. 4.4 ± 22 mmHg, p = 0.04). The degrees of annual decline in GFR did not differ between the distal RD group and conventional RD group ( p = 0.9) and were –2.7 ± 2.4 mL/min/1.73 m 2 /year and –2.7 ± 4.0 mL/min/1.73 m 2 /year, respectively. No significant changes in renal blood flow, albuminuria, MRI-based kidney size, and the number of patients with albuminuria and renal dysfunction were found during the study. Conclusions. Distal RDN in diabetic patients with RHT had a three-year safety profile and nephroprotective efficacy similar to those when the standard method was used despite a more significant reduction of blood pressure. Both modes of RD are likely to slow the progression of renal dysfunction in these patients.