This study examined the role played by neurohumoral factors in mediating the effects of beta-blocker therapy for congestive heart failure. Fifteen patients with congestive heart failure underwent beta-blocker therapy. Plasma norepinephrine and alpha-atrial natriuretic peptide concentrations decreased 2 weeks after initiation of beta-blocker therapy. Decrease in plasma norepinephrine level persisted for 6 months. Lymphocyte beta-adrenoceptor density increased 2 weeks after therapy but was not increased 6 months later. Left ventricular ejection fraction was unchanged 2 weeks after therapy, but it increased 6 months after introduction of beta-blockers. Plasma norepinephrine level decreased 2 weeks after the therapy in the responders (increase in ejection fraction > 0.10) but not in the nonresponders. Thus early reduction of neurohumoral factor levels preceded the late improvement of left ventricular contractile function and may therefore be partly responsible for the efficacy of beta-blocker therapy for congestive heart failure.