Background: Cardiac resynchronization therapy (CRT) is a well-established therapy for patients with heart failure (HF). However, 30% of HF patients do not show any improvement in clinical status after CRT implantation. In this study, we report our echocardiography-based CRT optimization methodology, in daily practice at our CRT referral center. Methods: We included 350 ambulatory patients, who were referred to our center for optimization after CRT implantation. A protocol-driven echocardiographic approach for adjusting mechanical dyssynchrony, whereby adjusting for ventriculoventricular (VV) delays with strain and atrioventricular (AV) delays with Doppler echocardiography was performed. We defined changes in left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) classes as outcome variables in the evaluation of the CRT outcomes. Results: Optimization was obtained in 288 (82%) patients. VV and AV timings were adjusted to 61% and 51%, respectively. In 3%, biventricular pacing was turned off and in 3% left ventricular (LV) only pacing was programmed. The LVEF and NYHA class showed significant improvements in all patients who underwent CRT optimization. Conclusions: CRT optimization remains valuable in improving LVEF and functional status measured using the NYHA class in all patients receiving CRT devices.