OBJECTIVE: The family of matrix metalloproteinases (MMPs) involved in fibrogenesis, but the effect of renal denervation (RDN) on their levels is currently insufficiently studied and highly controversial. The aim of study was to evaluate the change in MMPs and their inhibitors during 2 years after RDN in patients with resistant hypertension (RHTN) and type 2 diabetes mellitus (DM). DESIGN AND METHOD: Forty three patients with RHTN and type 2 DM were included in single-arm prospective interventional studies (protocol numbers NCT01499810 and NCT02667912 on ClinicalTrials.gov) (mean age 60.6 ± 8.8 years, mean office (systolic/diastolic) blood pressure (BP) 169.7/89.1 ± 19.2/15.2mmHg, HbA1c 6.7 ± 1.4%, 17(40%) men). All patients were undergone to ambulatory 24-hour BP and assessment of lab testes (plasma concentrations of MMP-9, MMP-2, tissue inhibitor of MMP type 1 (TIMP1), TIMP-1/MMP-2 and TIMP-1/MMP-9 ratios) at baseline and at 6-12-24 months follow-up. The patients were advised not to change their medication regimen during the study. RESULTS: At baseline 70%/16%/17% of patients had an elevated level of MMP-9/MMP-2/TIMP-1, respectively. At 6 months after RDN there was a significant decrease in mean 24-hour systolic/diastolic BP (SBP/DBP) (-8.8 [95%CI -1.3;-18.4]/-8.6 [95%CI -2.5;-4.7] mmHg, P < 0.05). The number of responders (patients with decrease in 24-hour SBP 10 mmHg and more) was 26 (61%). There were no significant changes in the mean levels of MMPs, TIMT1 and their ratios at 6-12-24 months follow up. At the same time, at 2 years after RDN there was a significant decrease in level of MMP-9 in responders compared with non-responders (-319.6[-2.3;-636.8] ng/mL, p = 0.04 vs 66.6 [221.4;-354.5] ng/mL, p = 0.63). CONCLUSIONS: Our data indicate the decrease in the MMP-9 level at 2 years after RDN only in the responders, that may be due to a decrease in the hemodynamic load and peripheral vasodilation that no longer requires the involving of proteolytic systems for an improvement in tissue blood flow.