OBJECTIVE This study examined the long-term (3-month) effects of nebivolol, a new beta-adrenergic blocking agent, on cardiac performance in patients with dilated cardiomyopathy. BACKGROUND Several beta-blocking drugs have been reported to have a beneficial hemodynamic effect in patients with dilated cardiomyopathy, but few data obtained in a placebo-controlled randomized study have addressed the mechanisms of improvement. METHODS Twenty-four patients with dilated idiopathic (n = 22) or ischemic (n = 2) cardiomyopathy (ejection fraction 0.15 to 0.40) in stable New York Heart Association functional class II or III were entered into a double-blind randomized trial of nebivolol, a new, potent, selective beta 1-antagonist. Exercise time, invasive hemodynamic data (12- and 24-h monitoring) and variables of left ventricular function were examined at baseline and after 3 months of orally administered nebivolol (1 to 5 mg/day, n = 11) or placebo (n = 13). RESULTS Heart rate decreased (group mean 85 to 71 beats/min vs. 87 to 87 beats/min with placebo) and stroke volume increased significantly (group mean 43 to 55 ml vs. 42 to 43 ml) with nebivolol; decreases in systemic resistance, systemic arterial pressure, wedge pressure and pulmonary artery pressure were not significantly different from those with placebo. Similar hemodynamic results were obtained in the catheterization laboratory. Analysis of high fidelity measurements of left ventricular pressure showed a decrease in left ventricular end-diastolic pressure in the nebivolol group (group mean 21 to 15 vs. 24 to 20 mm Hg with placebo) but no change in the maximal rate of pressure development or in two variables of left ventricular relaxation (maximal negative rate of change of left ventricular pressure [dP/dtmax] and the time constant tau). Left ventricular mass decreased (p = 0.04). Despite a decrease in heart rate with nebivolol, there was a slight decrease in left ventricular end-diastolic volume (p = NS). End-systolic volume tended to decrease (p = 0.07) despite no reduction in end-systolic stress. The net result was a significant increase in ejection fraction (group mean 0.23 to 0.33 vs. 0.21 to 0.23 with placebo), presumably as a result of an increase in contractile performance. This effect was corroborated by an increase in a relatively load-independent variable of myocardial performance. CONCLUSIONS Nebivolol improved stroke volume, ejection fraction and left ventricular end-diastolic pressure, not through a measurable reduction in afterload or a lusitropic effect, but by improving systolic contractile performance.