(1) Background: Periodic repetitive AV interval optimization using a device-based algorithm in cardiac resynchronization therapy (CRT) devices may improve clinical outcomes. There is an unmet need to successfully transform its application into clinical routine. (2) Methods: Non-invasive imaging of cardiac electrophysiology was performed in different device programming settings of the SyncAV®algorithm in 14 heart failure patients with left bundle branch block and a PR interval ≤ 250 milliseconds to determine the shortest ventricular activation time. (3) Results: the best offset time (to be manually programmed) permitting automatic dynamic adjustment of the paced atrioventricular interval after every 256 heart beats was found to be 30 and 50 milliseconds, decreasing mean native QRS duration from 181.6 ± 23.9 milliseconds to 130.7 ± 10.0 and 130.1 ± 10.5 milliseconds, respectively (p= 0.01); this was followed by an offset of 40 milliseconds (decreasing QRS duration to 130.1 ± 12.2 milliseconds;p= 0.08). (4) Conclusions: The herein presented NICE-CRT study supports the current recommendation to program an offset of 50 milliseconds as default in patients with left bundle branch block and preserved atrioventricular conduction after implantation of a CRT device capable of SyncAV®optimization. Alternatively, offset programming of 30 milliseconds may also be applied as default programming. In patients with no or poor CRT response, additional efforts should be spent to individualize best offset programming with electrocardiographic optimization techniques.