The purpose of the study was to evaluate the effect of long-term β 1-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or β 1-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the β 1-AR blockade group required mitral valve surgery (p = 0.23). β 1-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428) © 2012 American College of Cardiology Foundation.