This study was conducted to investigate the clinical impact of cardiac resynchronization device optimization. A series of 100 consecutive patients received cardiac resynchronization therapy. In the first 49 patients, an empirical atrioventricular delay of 120 ms was set, with simultaneous biventricular stimulation (interventricular VV interval = 0 ms). In the next 51 patients, systematic atrioventricular optimization was performed. VV optimization was also performed, selecting 1 VV delay: right or left ventricular preactivation (+30 or −30 ms) or simultaneous (VV interval = 0 ms), according to the best synchrony obtained by tissue Doppler–derived wall displacement. At follow-up, patients who were alive without cardiac transplantation and showed improvement of ≥10% in the distance walked in the 6-minute walking test were considered responders. There were no differences between the 2 groups at baseline. Left ventricular ejection fraction improved in the 2 groups, but left ventricular cardiac output improved only in the optimized group. At 6 months, patients with optimized devices walked slightly further in the 6-minute walking test (497 ± 167 vs 393 ± 123 m, p <0.01), with no differences in New York Heart Association functional class or quality of life compared with nonoptimized patients. Overall, the number of nonresponders were similar in the 2 groups (27% vs 23%, p = NS). In conclusion, the echocardiographic optimization of cardiac resynchronization devices provided a slight incremental clinical benefit at midterm follow-up. Simple and rapid methods to routinely optimize the devices are warranted.