Ventricular tachycardia in heart failure (HF) can initiate by nonreentrant mechanisms such as delayed after depolarizations. In an arrhythmogenic rabbit model of HF, we have shown that isoproterenol induces ventricular tachycardia in vivo and after contractions and transient inward currents in HF myocytes. To determine whether ₂-adrenergic receptor (₂-AR) stimulation contributes, we performed in vivo drug infusion, in vitro myocyte and biochemical studies. Intravenous zinterol (2.5 µg/kg) led to ventricular arrhythmias, including ventricular tachycardia up to 13 beats long in 4 of 6 HF rabbits (versus 0 of 5 controls, P<0.01), an effect blocked by ₂-AR antagonist ICI-118,551 (0.2 mg/kg). In field-stimulated myocytes (0.5 to 4 Hz, 37°C), ₂-AR stimulation (1 µmol/L zinterol+300 nmol/L ₁-AR antagonist CGP-29712A) induced after contractions and after–Ca transients in 88% of HF versus 0% of control myocytes (P<0.01). ₂-AR stimulation in HF (but not control) myocytes increased Ca transient amplitude (by 29%), sarcoplasmic reticulum (SR) Ca load (by 28%), the rate of [Ca]_i decline (by 28%; n=12, all P<0.05), and phospholamban phosphorylation at Ser16, but Ca current was unchanged. All of these effects in HF myocytes were blocked by ICI-118,551 (100 nmol/L). Although total -AR expression was reduced by 47% in HF rabbit left ventricular, ₂-AR number was unchanged, indicating more potent ₂-AR–dependent SR Ca uptake and arrhythmogenesis in HF. Human HF myocytes showed similar ₂-AR–induced after contractions, after transients, and enhanced Ca transient amplitude, SR Ca load and twitch [Ca]_i decline rate. Thus, ₂-AR stimulation is arrhythmogenic in HF, mediated by SR Ca overload-induced spontaneous SR Ca release and after contractions.