Secondary mitral regurgitation (MR) is frequent in patients with severely depressed left ventricular function. It increases mortality, and decreases exercise capacity. Its main mechanisms are multifactorial, related to apical and outward displacement of the papillary muscles, secondary to an enlarged and a more spherical left ventricle, causing increased subvalvar traction; mitral annular dilatation; and poor contraction of the left ventricle, with a slowed rate of rise of intraventricular pressure and slow closure of the leaflets. Since mechanical dyssynchrony is a major contributor factor to secondary MR, cardiac resynchronization therapy (CRT) could be considered as an alternative therapeutic option for MR, alone or in combination with surgical correction. Effects of CRT on secondary MR are acute and long-term, due to the reverse remodeling of the left ventricle. CRT reduces systolic MR by 30-40%, both at rest and during exercise, and abolishes diastolic MR, by increase of the closing forces and decrease of the tethering forces, acting on the mitral valve; decrease of the mitral annular dilatation represents a minor mechanism. Patients more likely to benefit should have moderate-to-severe MR (but not too severe), of nonischemic etiology, and high interpapillary muscles dyssynchrony. Effects are similar in patients with sinus rhythm and in patients with atrial fibrillation, and in patients with broad and narrow QRS complexes, provided that they have similar extent of dyssynchrony. Biventricular mode is the pacing modality of choice.