Nebivolol, unlike other selective β1-receptor blockers, induces vasodilation attributable to increased nitric oxide (NO) function. Autonomic function normally masks the contribution of this effect because of baroreflex buffering. We have previously shown that sildenafil lowers blood pressure (BP) in autonomic failure patients with supine hypertension. These patients, therefore, provide a unique model of hypertension devoid of autonomic modulation but sensitive to increases in NO function. To test the hypothesis that nebivolol would decrease BP in this patient population through a mechanism independent of β-blockade, we randomized 20 autonomic failure patients with supine hypertension (14 men, 69±2 yr) to receive a single oral dose of placebo, nebivolol 5 mg, metoprolol 50 mg (negative control) and sildenafil 25 mg (positive control) on separate nights in a double-blind, crossover study. Medications were given at 8 pm. Supine BP was monitored every 2 hr for 12 hr. Compared to placebo, sildenafil and nebivolol decreased systolic BP (SBP) during the night (P<0.001 and P=0.036, by mixed-effects model) with a similar maximal reduction in SBP 8 hr post drug (-20±6 and -24±9 mm Hg, respectively. Figure). Metoprolol, in contrast, had no significant effect on BP. Despite lowering nighttime BP, nebivolol did not worsen orthostatic tolerance the following morning (8am) compared to placebo. We conclude that nebivolol effectively lowers BP by a mechanism that does not involve β1-blockade and to a similar magnitude to that produced by NO potentiation with sildenafil. Nebivolol might be a useful alternative to treat patients with this condition.