Background: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality and improves symptoms in patients with systolic heart failure (HF) and ventricular dyssynchrony. This randomized, double-blind, controlled study evaluated whether optimizing the interventricular stimulating interval (V-V) to sequentially activate the ventricles is clinically better than simultaneous V-V stimulation during CRT. Methods: Patients with New York Heart Association (NYHA) III or IV HF, meeting both CRT and implantable cardioverter-defibrillator indications, randomly received either simultaneous CRT or CRT with optimized V-V settings for 6 months. Patients also underwent echocardiography-guided atrioventricular delay optimization to maximize left ventricular filling. The V-V optimization involved minimizing the left ventricular septal to posterior wall motion delay during CRT. The primary objective was to demonstrate noninferiority using a clinical composite end point that included mortality, HF hospitalization, NYHA functional class, and patient global assessment. Secondary end points included changes in NYHA classification, 6-minute hall walk distance, quality of life, peak VO2, and event-free survival. Results: The composite score improved in 75 (64.7%) of 116 simultaneous patients and in 92 (75.4%) of 122 optimized patients (P <.001, for noninferiority). A prespecified test of superiority showed that more optimized patients improved (P =.03). New York Heart Association functional class improved in 58.0% of simultaneous patients versus 75.0% of optimized patients (P =.01). No significant differences in exercise capacity, quality of life, peak VO 2, or HF-related event rate between the 2 groups were observed. Conclusions: These findings demonstrate modest clinical benefit with optimized sequential V-V stimulation during CRT in patients with NYHA class III and IV HF. Optimizing V-V timing may provide an additional tool for increasing the proportion of patients who respond to CRT.