A cardiac rhythm management system provides for assessment of cardiac mechanical dyssynchrony based on heart sound morphology and optimization of pacing parameters based on the effect of pacing on the cardiac mechanical dyssynchrony assessment. A degree of cardiac mechanical dyssynchrony is measured by the time delay between tricuspid valve closure and mitral valve closure and/or the time delay between pulmonary valve closure and aortic valve closure. A cardiac resynchronization therapy is optimized by determining therapy parameters to provide an approximately minimum degree of cardiac mechanical dyssynchrony by cardiac pacing.