Cardiac resynchronization therapy (CRT) has been shown to reduce functional mitral regurgitation (MR). The aims of this study were to analyze the underlying mechanisms leading to this reduction and to identify the best candidates with functional MR for this therapy. Changes in mitral geometry, left ventricular (LV) remodeling, and LV synchrony were studied in patients who underwent CRT acutely and at 6- and 12-month follow-up. Of 151 patients (mean age 69 +/- 9 years, 82% men) who underwent CRT, 57 (38%) had nontrivial MR (regurgitant orifice area > or =10 mm(2)). The median reduction of MR with CRT was 18% acutely and 38% at 12-month follow-up. CRT induced an acute improvement in LV systolic function (LV dP/dt from 508 +/- 143 to 700 +/- 249 mm Hg, p <0.05) and a reduction in dyssynchrony (interventricular delay from 51 +/- 31 to 29 +/- 27 ms, p <0.05). At 12-month follow-up, additional reverse global and local LV remodeling (LV end-systolic volume from 183 +/- 77 to 151 +/- 50 ml, tenting area from 3.36 +/- 0.98 to 2.78 +/- 0.75 cm, p <0.05 for both) and a reduction in LV dyssynchrony (septal-lateral delay from 90 +/- 63 to 53 +/- 42 ms, p <0.05) were found. Significant reductions in MR were found in 28 patients (49%) and similarly observed in either ischemic MR or functional MR of other causes. Baseline mitral tenting area was the strongest predictor of significant MR reduction with CRT. In conclusion, CRT induced acute and sustained reductions in functional MR in almost 50% of patients by initially improving LV systolic function and dyssynchrony; long-term reverse LV remodeling contributed to this sustained effect. Patients with larger mitral valve tenting areas are less amenable to benefit from CRT.