Cardiac resynchronization therapy (CRT) induces left ventricular (LV) reverse remodeling by synchronizing LV mechanical activation. We evaluated changes in segmental LV activation after CRT and related them to CRT response. A total of 292 patients with heart failure (65 ± 10 years, 77% men) treated with CRT underwent baseline echocardiographic assessment of LV volumes and ejection fraction. Time-to-peak radial strain was measured for 6 midventricular LV segments with speckle-tracking strain imaging. Moreover, the time difference between the peak radial strain of the anteroseptal and the posterior segments was calculated to obtain LV dyssynchrony. After 6 months, LV volumes, segmental LV mechanical activation timings, and LV dyssynchrony were reassessed. Response to CRT was defined as ≥15% decrease in LV end-systolic volume at 6-month follow-up. Responders (n = 177) showed LV resynchronization 6 months after CRT (LV dyssynchrony from 200 ± 127 to 85 ± 86 ms; p <0.001) by earlier activation of the posterior segment (from 438 ± 141 to 394 ± 132 ms; p = 0.001) and delayed activation of the anteroseptal segment (from 295 ± 155 to 407 ± 138 ms; p <0.001). In contrast, nonresponders (n = 115) experienced an increase in LV dyssynchrony 6 months after CRT (from 106 ± 86 to 155 ± 112 ms; p = 0.001) with an earlier activation of posterior wall (from 391 ± 139 to 355 ± 136 ms; p = 0.039) that did not match the delayed anteroseptal activation (from 360 ± 148 to 415 ± 122 ms; p = 0.001). In conclusion, responders to CRT showed LV resynchronization through balanced lateral and anteroseptal activations. In nonresponders, LV dyssynchrony remains, by posterior wall preactivation and noncompensatory delayed septal wall activation.