BACKGROUNDCurrently there is no consensus regarding which add-on therapy to use in resistant hypertension. This study was designed to compare two treatment options, spironolactone (SPR) versus dual blockade of the renin–angiotensin–aldosterone system (RAAS). METHODSForty-two patients with true resistant hypertension were included in the study. An open-label prospective crossover design was used to add a second RAAS blocker to previous treatment and then SPR following 1 month of wash-out. BP was measured in the office and by ambulatory blood pressure monitoring (ABPM). Changes in laboratory tests were also studied for both treatments. The predictive values of aldosterone–renin ratio (ARR) and serum potassium of determining the antihypertensive response were analyzed for both arms. RESULTSFollowing the first stage of dual blockade, SBP dropped significantly both in office (reduction of 12.9 ± 19.2 mmHg)) and by ABPM (reduction of 7.1 ± 13.4 mmHg). Office DBP was unchanged but was significantly reduced as measured by ABPM (3.4 ± 6.2 mmHg). On SPR treatment, office BP was reduced 32.2 ± 20.6/10.9 ± 11.6 mmHg. By ABPM the reduction was 20.8 ± 14.6/8.8 ± 7.3 mmHg (P < 0.001). The BP control was achieved by 25.6% of patients in dual blockade and 53.8% in SPR with office blood pressure. By ABPM, 20.5% were controlled on dual blockade and up to 56.4% with SPR. Serum potassium was a weak inverse predictor of the blood pressure-lowering effect of SPR. CONCLUSIONSPR has a greater antihypertensive effect than dual blockade of the RAAS in resistant hypertension. SPR at daily doses of 25–50 mg shows a potent antihypertensive effect when added to prior regimes of single RAAS axis blockade in patients with resistant arterial hypertension.