To identify the role of the myocardial β-adrenergic pathway in congestive heart failure, we examined β-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in β-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P<0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P>0.05). We conclude that in failing human hearts a decrease in β-receptor density leads to subsensitivity of the β-adrenergic pathway and decreased β-agonist-stimulated muscle contraction. Regulation of β-adrenergic receptors may be an important variable in cardiac failure. (N Engl J Med. 1982; 307:205–11.) THE hallmark of congestive heart failure is decreased myocardial inotropic function. Although previous studies in animal models and human tissue have documented a variety of biochemical changes associated with heart failure,1,2 none of these changes appears to be adequate to explain the marked decrease in contractile function that occurs in advanced heart-muscle disease. Perhaps the most likely location for a primary abnormality in cardiac failure is in the specialized cellular components that modulate calcium flux,3 some of which reside in the sarcolemma. One component of this system is the β-adrenergic receptor; through combination with a hormone agonist, this receptor may.