Objective: Recent studies have suggested improved clinical outcomes with left bundle branch area pacing (LBBAP) compared to biventricular pacing (BIVP) for cardiac resynchronization therapy (CRT). However, successful left bundle branch pacing (LBBP) is not always achieved and left ventricular septal pacing (LVSP) is often accepted as an alternative.Methods: In this prospective multicenter observational study, LBBP was compared to LVSP and BIVP in patients undergoing CRT. The primary outcome was a composite of heart failure (HF) related hospitalization and all-cause mortality. Secondary outcomes included individual components of the primary outcome, postprocedural New York Heart Association functional class, electrocardiographic, and echocardiographic parameters. Results: A total of 415 patients were included (LBBP n= 141, LVSP n= 31, BIVP n= 243), with a median follow-up time of 399 [IQR: 249.5-554.8] days. The primary outcome occurred in 23.4% in the LBBP vs 51.6% in the LVSP group (HR 0.36; 95% CI 0.197-0.654; p= 0.001), driven by a 64.9% relative risk reduction in HF-related hospitalizations (17% vs. 48.4%; HR 0.282; 95% CI 0.147-0.539; p <0.001) without differences in all-cause mortality (11.3% vs. 19.4%; p= 0.282). LBBP was also associated with lower incidence of the primary outcome when compared to BIVP (HR 0.503, 95% CI 0.341-0.743, p <0.001). There were no significant differences in outcomes between LVSP and BIVP.Conclusion: In patients undergoing CRT, LBBP is associated with improved outcomes compared to LVSP and BIVP, however outcomes between BIVP and LVSP are similar. Thus, LBBP could be the preferred strategy in patients undergoing CRT.