Background: The effect of cardiac resynchronization therapy (CRT) on left ventricular wall thickness and left ventricular mass (LVM) is unknown. Objectives: To evaluate the effects of CRT on septal and posterior wall thickness (SWT and PWT) and LVM in patients with left bundle branch block (LBBB) and non-LBBB vs implantable cardioverter-defibrillator patients and to assess the relationship between CRT-induced changes and cardiac events. Methods: We investigated 843 patients with LBBB and 366 patients with non-LBBB enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT) trial to analyze changes in SWT, PWT, and LVM at 12 months and subsequent outcome. The primary end point was heart failure or death; secondary end points included ventricular tachycardia, ventricular fibrillation, or death. Results: In LBBB patients, reduction in SWT, PWT, and LVM was more pronounced in CRT defibrillator (CRT-D) than in implantable cardioverter-defibrillator (SWT:-6.7%±4.4% vs-1.0%±1.9%; PWT:-6.4%±4.3% vs-0.8%±1.9%; LVM:-23.6%±9.9% vs-5.1%±5.1%; P<.001 for all). In CRT-D patients with non-LBBB, LVM reduction was less pronounced; however, changes in SWT and PWT were comparable. Changes in LVM correlated with changes in left ventricular end-diastolic volume. In CRT-D patients with LBBB, reduction in SWT and LVM was associated with reduction in heart failure/death (SWT: hazard ratio 0.94; 95% confidence interval 0.89-0.99 per percent change; P =.03) and ventricular tachycardia/ventricular fibrillation/death (SWT: hazard ratio 0.95; 95% confidence interval 0.91-1.00; P =.04). CRT-D patients with non-LBBB did not show favorable reduction in clinical or arrhythmic end points related to changes in SWT, PWT, or LVM. Conclusions: CRT-D was associated with significant reduction in SWT, PWT, and LVM in patients with LBBB along with left ventricular volume changes and associated favorable clinical and arrhythmia outcomes. © 2013 Heart Rhythm Society. All rights reserved.