T hirteen percent of global mortality has been associated with arterial hypertension. Approximately 34% of the total adult population worldwide is hypertensive, and 13% of this segment of the population is further categorized as having resistant hypertension (RHTN).1 Criteria for the diagnosis of RHTN are the following: any patient requiring ≥3 antihypertensive drugs, including a diuretic, and still maintaining a blood pressure (BP) >140/90 mm Hg.2 RHTN has been previously described as a multifactorial phenomenon involving multiple biological mechanisms; however, the hyperactivity of the sympathetic nervous system plays a paramount role in the onset, maintenance, and progression of RHTN. 3 The renal sympathetic nervous system, composed of afferent and efferent nerves, courses immediately adjacent to the wall of the renal artery. 4 The afferent renal sensory nerves, with neuronal cell bodies located in the ipsilateral dorsal root ganglia, modulate the central sympathetic outflow by providing sensory information from mechanoreceptors and chemoreceptors in the renal tissue. Renal injuries (ie, hypoxia) increase afferent sensory signals, resulting in an increase in efferent sympathetic nerve activity, peripheral arterial vasoconstriction, and subsequent increase in arterial BP. The efferent renal sympathetic nerves transmit signals from the central sympathetic nervous system to the kidneys (ie, renal vasculature, tubules, and juxtaglomerular apparatus). Efferent renal sympathetic activity is moderated by an inhibitory renorenal reflex and central sympathetic nervous system outflow. Elevated efferent renal sympathetic activity increases sodium reabsorption and renin release and causes renal arterial vasoconstriction, leading to hypertension. Catheter-based ablation of afferent and efferent sympathetic nerves surrounding the renal arteries has been proposed Background-Renal denervation (RDN) emerged as a therapeutic option for resistant hypertension. Nerve regrowth after RDN has been questioned. We aimed to characterize the nerve response after RDN. Methods and Results-Swine underwent bilateral RDN and were followed up for 7, 30, and 90 days and evaluated with S100 (Schwann cell), tyrosine hydroxylase (TH; efferent nerves), and growth-associated protein 43 (neurite regeneration) markers. At 7 days, nerve changes consisted of necrosis associated with perineurial fibrosis and distal atrophy with inflammation. At 30 days changes were substituted by healing changes (ie, fibrosis). This response progressed through 90 days resulting in prominent neuroma formation. Immunohistochemistry at 7 days: TH staining was strongly decreased in treated nerves. Early regenerative attempts were observed with strongly TH and growth-associated protein 43 positive and weak S100 disorganized nerve sprouts within the thickened perineurium. Distal atrophic nerves show weak staining for all 3 markers. At 30 days, affected nerves show a weak TH and S100 staining. Evident growth-associated protein 43+ disorganized neuromatous tangles in the thick...