We report the case of a patient with severe left ventricular systolic dysfunction and left bundle branch block in whom cardiac resynchronization therapy (CRT) was optimized by tissue Doppler imaging. A horizontal mechanical asynchrony index was derived from tissue Doppler regional longitudinal strain rate profiles as the time difference at the onset of shortening between septum, lateral, anterior and inferior walls. The interventricular delay was modulated in order to achieve the smallest asynchrony index; on the basis of this parameter a sequential (S)-CRT with a left ventricular pre-excitation of 20 ms was definitively programmed. This optimized S-CRT was followed by an acute improvement in systolic cardiac performance and by a long-term (12 months) clinical benefit as well as by a documented decrease in LV chamber size due to a true reverse remodeling effect. Thus, in some patients S-CRT may be more effective than conventional CRT. Tissue Doppler-derived strain rate analysis can provide information on the degree of left intraventricular asynchrony allowing the modulation of a tailored interventricular delay.