Background— Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional α 2C -adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel β-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether α 2C -AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results— In the β-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and α 2C -AR gene polymorphisms (α 2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were α 2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153±57 pg/mL, P =0.012 compared with placebo versus decrease of 50±13 pg/mL in α 2C wild type, P =0.0005 versus placebo; P =0.010 by interaction test). α 2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P =0.80), whereas bucindolol-treated subjects who were wild type for the α 2C -AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P =0.025). Conclusions— In the β-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by α 2C receptor genotype.