Background: Abnormal glucose metabolism and insulin resistance have been associated with heart failure (HF) incidence, severity, and mortality. Metabolic parameters such as hepatic glucose production may be altered by β-adrenoceptor antagonists in patients with HF. Objective: To evaluate the effects of metoprolol succinate or carvedilol uβtitration on fasting glucose, insulin resistance, and β2-mediated glucose production in patients with chronic HF. Methods: This was a prospective, randomized, active comparator study in 15 patients with American Heart Association/American College of Cardiology Stage C systolic dysfunction HF that was stabilized with medical therapy. Participants were randomized to receive metoprolol succinate 25 mg daily or carvedilol 3.125 mg twice daily. Metoprolol was titrated to a target of 200 mg daily, and carvedilol was titrated to 25 mg twice daily over 8 weeks. Insulin resistance as assessed by the homeostatic model and terbutaline-induced glucose production (area under the curve from 0 to 180 ⋯ [AUC0-180]) were assessed at baseline and at 4 subsequent β-blocker titration visits over 8 weeks. Results: In all 15 patients, terbutaline-induced glucose AUC0-180 decreased (p = 0.001) as β-blocker doses increased. A significant reduction in glucose AUC 0-180 compared with baseline was noted only in patients taking metoprolol 100 mg daily (-2424.6 mg/dL·min; 95% CI 372.6 to -4478.4) and 200 mg daily (-2437.2 mg/dL·min; 95% CI -15.1 to -4604.4) and was not observed in those taking carvedilol. After βblocker titration, fasting glucose concentrations for the metoprolol and carvedilol groups were 86.9 mg/dL (95% CI 89.8 to 101.6) and 95.7 mg/dL (95% CI 89.8 to 101.6), respectively (p = 0.027), adjusted for baseline values. There was no significant difference between the effect of metoprolol and carvedilol on insulin resistance. Conclusions: Increasing doses of βblockers are associated with decreased βz mediated glucose production in HF. Metoprolol succinate, but not carvedilol, decreases hepatic glucose production at doses commonly used in HF.