BACKGROUND: Although some guidelines recommend Renal denervation (RDN) as an alternative to anti-HTN medications, there are concerns about its efficacy and safety. We aimed to evaluate the benefits and harms of RDN in a systematic review and meta-analysis of sham-controlled randomized clinical trials (RCT). METHODS: Databases were searched until September 10th, 2024, to identify RCTs evaluating RDN for treating URH versus sham control. The primary outcomes were the change in office and ambulatory 24-h systolic (SBP) and diastolic blood pressure (DBP). Secondary outcomes were changes in daytime and nighttime SBP and DBP, home BP, number of anti-HTN drugs, and related complications. Mean differences (MD) and relative risks (RR) described the effects of RDN on BP and complications, respectively, using random effects meta-analyses. GRADE methodology was used to assess the certainty of evidence (COE). RESULTS: We found 16 included sham-controlled RCTs [RDN (n = 1594) vs. sham (n = 1225)]. RDN significantly reduced office SBP (MD -4.26 mmHg, 95% CI: -5.68 to -2.84), 24 h ambulatory SBP (MD -2.63 mmHg), office DBP (MD -2.15 mmHg), 24-h ambulatory DBP (MD -1.27 mmHg), and daytime SBP and DBP (MD -3.29 and 2.97 mmHg), compared to the sham. The rate of severe complications was low in both groups (0%-2%). The heterogeneity was high among most indices, and CoE was very low for most outcomes. CONCLUSION: RDN significantly reduced several SBP and DBP outcomes versus sham without significantly increasing complications. This makes RDN a potentially effective alternative to medications in URH.