Left ventricular (LV) lead position may be an important factor for delivering effective cardiac resynchronization therapy (CRT). We therefore aimed to evaluate the effects of LV lead position, stratified by native QRS morphology, regarding the clinical outcome. A total of 1295 CRT-implanted patients were retrospectively evaluated. LV lead position was classified as lateral, anterior, inferior, or apical, and was determined using the left and right anterior oblique X-ray views. Kaplan Meier and Cox regression were performed to evaluate the effects on all-cause mortality and heart failure hospitalization, and the potential interaction between LV lead position and native ECG morphologies. A total of 1295 patients were included. Patients were aged 69 ± 7 years, 20% were female, 46% received a CRT-Pacemaker (vs. CRT-Defibrillator), mean LVEF was 25% ± 7%, and median follow-up was 3.3 years [IQR 1.6-5-7 years]. Eight hundred and eighty-two patients (68%) had a lateral LV lead location, 207 (16%) anterior, 155 (12%) apical, and 51 (4%) inferior. Patients with lateral LV lead position had larger QRS reduction (-13 ± 27 ms vs. -3 ± 24 ms, p < .001). Non-lateral lead location was associated with a higher risk for all-cause mortality (HR 1.34 [1.09-1.67], p = .007) and heart failure hospitalization (HR 1.25 [1.03-1.52], p = .03). This association was strongest for patients with native left or right bundle branch block, and not significant for patients with prior paced QRS or nonspecific intraventricular conduction delay. In patients treated with CRT, non-lateral LV lead positions (including apical, anterior, and inferior positions) were associated with worse clinical outcome and less reduction of QRS duration. This association was strongest for patients with native LBBB or RBBB.