<jats:p>Renal denervation and spironolactone have both been proposed for the treatment of resistant hypertension, but their effects on preclinical target organ damage have not been compared. Twenty‐four patients with 24‐hour systolic blood pressure ≥140 mm Hg despite receiving three or more full‐dose antihypertensive drugs, one a diuretic, were randomized to receive spironolactone or renal denervation. Changes in 24‐hour blood pressure, urine albumin excretion, arterial stiffness, carotid intima‐media thickness, and left ventricular mass index were evaluated at 6 months. Mean baseline‐adjusted difference between the two groups (spironolactone vs renal denervation) at 6 months in 24‐hour systolic blood pressure was −17.9 mm Hg (95% confidence interval [<jats:styled-content style="fixed-case">CI</jats:styled-content>], −30.9 to −4.9; <jats:italic>P</jats:italic> = .01). Mean baseline‐adjusted change in urine albumin excretion was −87.2 (95% <jats:styled-content style="fixed-case">CI</jats:styled-content>, −164.5 to −9.9) and −23.8 (95% <jats:styled-content style="fixed-case">CI</jats:styled-content>, −104.5 to 56.9), respectively (<jats:italic>P </jats:italic>=<jats:italic> </jats:italic>.028). Mean baseline‐adjusted variation of 24‐hour pulse pressure was −13.5 (95% <jats:styled-content style="fixed-case">CI</jats:styled-content>, −18.8 to −8.2) and −2.1 (95% <jats:styled-content style="fixed-case">CI</jats:styled-content>, −7.9 to 3.7), respectively (<jats:italic>P </jats:italic>=<jats:italic> </jats:italic>.006). The correlation of change in 24‐hour systolic blood pressure with change in log‐transformed urine albumin excretion was <jats:italic>r </jats:italic>= .713 (<jats:italic>P </jats:italic><<jats:italic> </jats:italic>.001). At 6 months there was a reduction in albuminuria in patients with resistant hypertension treated with spironolactone as compared with renal denervation.</jats:p>