Blood pressure (BP) reductions when combining blockers of the renin-angiotensin system (RAS) and β-blockers have generally not been shown to be greater than for individual agents, possibly because of overlapping mechanisms of action. The authors tested the additivity of the β-blocker nebivolol, which has vasodilating activity, with the angiotensin-converting enzyme inhibitor lisinopril in patients with stage 2 diastolic hypertension. The BP effects of placebo (n=93), nebivolol 5 mg to 20 mg daily (n = 185), lisinopril 10 mg to 40 mg daily (n=189), and nebivolol 5 mg to 20 mg + lisinopril 10 mg to 40 mg (n=189) during 6 weeks of treatment were compared. The primary end point was change in diastolic BP (DBP). For the full cohort, baseline BP was 163.8/104.4 mm Hg, mean age was 49.2 years, 58% were men, 62% were white, and 34% were black. DBP fell by 17.2 ± 10.2 mm Hg with the combination, greater than placebo (8.0 ± 9.2, P<.0001), nebivolol (13.3 ± 8.9, P=.0010), and lisinopril (12.0 ± 9.8, P<.0001). For systolic BP, corresponding reductions were 19.2 ± 19.8 mm Hg, 9.9 ± 16.4 (P<.0001 vs combination), 14.4 ± 14.1 (P=.0470), and 16.1 ± 17.2 (P=.0704). Adverse event rates were similar in all groups. This study demonstrated the potential antihypertensive benefits of combining nebivolol with a RAS blocker.