Background Data on the impact of right ventricular (RV) lead location on clinical outcome and ventricular tachyarrhythmias in cardiac resynchronization therapy with defibrillator (CRT-D) patients are limited. Objective To evaluate the impact of different RV lead locations on clinical outcome in CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial. Methods We investigated 742 of 1089 CRT-D patients (68%) with adjudicated RV lead location enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial to evaluate the impact of RV lead location on cardiac events. The primary end point was heart failure or death; secondary end points included ventricular tachycardia (VT), ventricular fibrillation (VF), or death and VT or VF alone. Results Eighty-six patients had the RV lead positioned at the RV septal or right ventricular outflow tract region, combined as nonapical RV group, and 656 patients had apical RV lead location. There was no difference in the primary end point in patients with nonapical RV lead location versus those with apical RV lead location (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.54-1.80; P =.983). Echocardiographic response to CRT-D was comparable across RV lead location groups (P >.05 for left ventricular end-diastolic volume, left ventricular end-systolic volume, and left atrial volume percent change). However, nonapical RV lead location was associated with significantly higher risk of VT/VF/death (HR 2.45; 95% CI 1.36-4.41; P =.003) and VT/VF alone (HR 2.52; 95% CI 1.36-4.65; P =.002), predominantly in the first year after device implantation. Results were consistent in patients with left bundle branch block. Conclusions In CRT-D patients, there is no benefit of nonapical RV lead location in clinical outcome or echocardiographic response. Moreover, nonapical RV lead location is associated with an increased risk of ventricular tachyarrhythmias, particularly in the first year after device implantation. © 2013 Heart Rhythm Society.