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Background Microvascular impairment is well documented in hypertension. We investigated the effect of renal sympathetic denervation (RDN) on cardiac and peripheral microvasculature in patients with treatment-resistant essential hypertension (TRH). Methods A randomized, single centre, double-blinded, sham-controlled clinical trial. Fifty-eight patients with TRH (ambulatory systolic BP (ASBP) ≥ 145 mm Hg) despite stable treatment were randomized to RDN or SHAM. RDN was performed with the unipolar Medtronic Flex catheter. Coronary flow reserve (CFR) and coronary- and forearm minimum vascular resistance (C-Rmin and F-Rmin) were determined using transthoracic Doppler echocardiography and F-Rmin with venous occlusion plethysmography at baseline and at six-months follow-up. Results RDN was performed with 5.3 ± 0.2 lesions in the right renal artery and 5.4 ± 0.2 lesions in the left. Baseline ASBP was 152 ± 2 mm Hg (RDN, n = 29) and 154 ± 2 mm Hg (SHAM, n = 29). Similar reductions in MAP were seen at follow up (− 3.5 ± 2.0 vs. − 3.2 ± 1.8, P = 0.92). Baseline CFR was 2.9 ± 0.1 (RDN) and 2.4 ± 0.1 (SHAM), with no significant change at follow-up (0.2 ± 0.2 vs. − 0.1 ± 0.2, P = 0.57). C-Rmin was 1.9 ± 0.3 (RDN) and 2.7 ± 0.6 (SHAM) (mm Hg min/ml pr. 100 g) and did not change significantly (0.3 ± 0.5 vs. − 0.4 ± 0.8, P = 0.48). F-Rmin was 3.6 ± 0.2 (RDN) and 3.6 ± 0.3 (SHAM) (mm Hg min/ml pr. 100 ml tissue) and unchanged at follow-up (4.2 ± 0.4 vs. 3.8 ± 0.2, P = 0.17). Left ventricular mass index was unchanged following RDN (− 4 ± 7 (RDN) vs. 3 ± 5 (SHAM) (g/m 2 ) P = 0.38). Conclusion The current study does not support positive effects of RDN on microvascular impairment in TRH. [ABSTRACT FROM AUTHOR]