1. Clinical studies have shown different effects of beta-blockers on the beta-adrenergic system, tolerability and outcome in patients with heart failure. 2. The study examines beta-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3. Radioligand binding studies ([(125)I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4. Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable binding. 5. All beta-blockers antagonized isoprenaline-induced enhancement of contractility. 6. In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89. 4+/-2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7. It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8. Differences in intrinsic activity may contribute to differences in beta-adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.