In 20 patients with severe congestive heart failure (CHF), we studied the effects of the beta-adrenergic agonist pirbuterol compared to placebo in both an acute double-blind randomized trial and after long-term treatment. Acutely, pirbuterol patients (n = 10) demonstrated a significant rise in cardiac index (2.2 ± 0.14 to 3.2 ± 0.32 L/min/m 2), stroke index (26 ± 2.6 to 35 ± 2.9 ml/beat/m 2), stroke work index (22 ± 2.4 to 30 ± 2.7 gm · m/m 2), and ejection fraction (22 ± 4 to 30 ± 5%). These hemodynamic variables did not significantly change in placebo patients (n = 10). After 3 weeks of pirbuterol therapy, 14 patients (70%) were symptomatically improved and were continued on the drug for another 3 weeks; 13 of 14 patients who were symptomatically improved underwent restudy. Compared to pretreatment baseline, there was continued improvement in cardiac index (2.5 ± 0.16 to 3.2 ± 0.24 L/min/m 2), stroke index (30 ± 2.5 to 38 ± 2.9 ml/beat/m 2), stroke work index (26 ± 2.3 to 35 ± 3.1 gm · m/m 2), and ejection fraction (24 ± 1 to 28 ± 4%). Patients more frequently improved were those with nonischemic cardiomyopathy and those with higher initial ejection fractions. These results demonstrate the acute beneficial effects of oral pirbuterol versus placebo in a double-blind randomized trial. Improvement was maintained during long-term therapy in the majority of CHF patients.