We related two common B2-AR gene polymorphism (the substitution of Arg with Gly at the position 16 and that of Gln with Glu at the position 27) with the long-term response to beta-blocker therapy (BB) with either carvedilol (35±19 mg/day, 113 patients) or metoprolol (89±48 mg/day, 37 patients) in patients with heart failure (HF) who underwent MUGA and Swan-Ganz catheterization before and after 9-18 months of BB. The Arg16Gly polymorphism had no relation with the response to BB. In contrast, the homozygosis for the Glu27 polymorphism, associated with a reduced agonist-promoted B2-AR downregulation and greater B2-AR function and sensitivity, was predictive of a greater response to carvedilol. The Glu27 homozygosis was found in 23 patients while 51 were heterozygotes and the remaining 76 had the "wild type" Gln27 homozygosis. Before BB, the Glu27 homozygotes had, compared with the others, a similar resting LVEF (23±6 vs. 22±7%) and pulmonary wedge pressure (PWP, 26±12 vs. 24±10 mm Hg), a higher cardiac index (CI, 2.9±0.6 vs. 2.5±0.6 L/m/m²; p=0.004) and stroke volume index (SVI, 36±10 vs. 31±9 mL/bt/m², p=0.002) with lower systemic vascular resistance (SVR, 1275±316 vs. 1481±393 d*s*cm-5, p=0.02). After BB, the Glu27 homozygotes showed a greater change in the EF (14±13 vs. 8±9 absolute units, p=0.01), PWP (-10±10 vs. -6±8 mm Hg, p=0.09) and SVI (14±9 vs. 9±9 mL/bt/m²; p=0.03). Cause of HF, baseline systolic blood pressure and the Gln27Glu polymorphisms were the only variables independently related to the change in the EF at multivariate analysis. Thus, the Glu27 gene polymorphism, which is related to a greater B2-AR sensitivity, is associated with less impairment in the LV function before BB therapy and with its greater improvement after long-term carvedilol administration.