In heart failure, the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenoreceptor (beta2-AR) gene are associated with exercise-capacity, clinical outcomes and response to beta-AR blocker therapy. Whether beta2-AR gene variants mediate these effects in-part through an impact on cardiac structural remodeling and pump function independent of the effects of beta-blockers is uncertain. We evaluated whether the Arg16Gly and Gln27Glu variants of the beta2-AR gene predict left ventricular ejection fraction (LVEF) and LV end diastolic diameter (LVEDD) in patients with idiopathic dilated cardiomyopathy (IDC) before and 6 months after receiving standard medical therapy other than beta-AR blockers. In all, 394 patients with IDC and 393 age and gender-matched controls were genotyped for the beta2-AR gene variants using restriction-fragment length polymorphism-based techniques. LVEF and dimensions were determined in 132 patients (of whom 71 were newly diagnosed) both at baseline and after 6 months. Genotype of neither variant was associated with the presence of IDC. Moreover, beta2-AR genotype did not determine LVEF or LV dimensions prior to initiating therapy. After 6 months of therapy, LVEF increased by 7.1+/-1.0 absolute units (P<0.0001) and LVEDD decreased by 0.27+/-0.06 cm (P<0.02). Adjusting for baseline values as well as gender, age, and type of angiotensin-converting enzyme inhibitor therapy received, genotype was associated with neither final LVEF and LVEDD, nor change in LVEF and LVEDD. In conclusion, these data suggest that in heart failure, the functional Arg16Gly and Gln27Glu variants of the beta2-AR gene have no independent effect on adverse structural remodeling and pump function.