Objective: Randomized controlled trials have shown that renal denervation lowers office and ambulatory blood pressure. However, the clinical environment of controlled trials is different from that characterizing medical practice, making real-life data appropriate to provide information on a number of issues, e.g. whether renal denervation is followed by a change in the intensity and type of antihypertensive drug use. The aim of the present study was to evaluate whether patients undergoing renal denervation procedure in a real-life setting have a reduction in antihypertensive drug prescription over the subsequent years. Design and method: Using the healthcare utilization database of the Lombardy Region (Italy), the 136 patients who, during the period 2011–2016, were prescribed four or more antihypertensive drugs and underwent renal denervation were included in the study cohort. The number and type of antihypertensive drugs were assessed over the year before and during the three-year period after renal denervation. Hospitalizations for cardiovascular diseases were also assessed during the three years before and during the three years after renal denervation. Results: The median age of the patients was 67 years and 68% of them were men. Based on a multisource comorbidity score, about 40% of patients showed a poor or very poor clinical status. Before renal denervation, about 80% of the patients were prescribed four or five antihypertensive drugs. The number of drugs decreased after the denervation: after three years, patients prescribed 4/5 drugs were 57% and patients prescribed six drugs decreased from 18% to 2%. Reduced prescription extended to all antihypertensive drugs throughout the post-denervation period. Compared to the year before the denervation, after three years prescription of diuretics was reduced by 15%, calcium channel blockers by 21%, angiotensin-converting enzyme inhibitors by 32%, angiotensin receptor blockers by 22%, beta-blockers by 20%, alfa-blockers by 30%, and mineralocorticoid receptor antagonists by 30%. Hospitalizations for cardiovascular diseases did not show appreciable differences between the two periods (before and after the renal denervation). Conclusions: In the real-life setting, patients who underwent renal denervation had a clearcut reduction in antihypertensive drug prescription over the following years.