We tested a once-a-day antihypertensive regimen using minoxidil, nadolol, and a diuretic in 55 patients with resistant hypertension. Forty-seven patients had evidence of end-organ damage. Twelve had mild renal insufficiency (serum creatinine concentration, 2.5 +/- 0.3 mg/dL). In 34 patients, treatment with nadolol and a diuretic was started with minoxidil added one to four weeks later. In the remainder, minoxidil, nadolol, and a diuretic were begun simultaneously because of severe hypertension. Initial supine and standing blood pressure (BP) in the 55 patients were 186 +/- 4/111 +/- 2 and 180 +/- 4/108 +/- 2 mm Hg, respectively. After 7 +/- 1 weeks, BP was controlled in 46 patients (84%) with the supine and standing BP reduced to 140 +/- 3/80 +/- 1 and 134 +/- 3/80 +/- 1, respectively. In six patients, BP was controlled but intolerable side effects occurred, making the regimen therapeutically successful in 40 patients (73%). The BP remained controlled during a follow-up of 43 +/- 5 weeks. In 31 patients, BPs measured 24 hours after the last dose were not different from random measurements. Mean serum creatinine levels remained stable in the 12 patients with renal insufficiency.