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Objectives: This study hypothesized that the shorter intrinsic PR interval observed in women allows a greater degree of fusion with intrinsic conduction, achieving a shorter QRS interval duration and, thus, a better response., Background: Women benefit more from cardiac resynchronization therapy (CRT) than men. However, the reason for this difference remains elusive., Methods: A cohort of 180 patients included in the BEST (Fusion based optimization in resynchronization therapy [ECG Optimization of CRT: Evaluation of Mid-Term Response]; NCT01439529) study were retrospectively analyzed. Patients were initially randomized to either nonoptimized CRT (NON-OPT group; n = 89) or electrocardiographically optimized CRT based on the fusion-optimized intervals (FOI) method (FOI group; n = 91). Echocardiographic response was defined as a >15% decrease in left ventricular end-systolic volume at the 12-month follow-up., Results: The basal PR interval was shorter in women as compared to men. In the NON-OPT group, CRT resulted in a shorter paced QRS interval in women than in men (134 ± 21 ms vs. 151 ± 21 ms, respectively; p = 0.003, 95% confidence interval [CI]: -27 to -5.6) and better response in women than in men: 70.4% vs. 46.4%, respectively (odds ratio: 0.37; p = 0.04; 95% CI: 0.14 to 0.97). There were no differences in paced QRS interval duration (126 ± 13 ms vs. 129 ± 17 ms; p = 0.47) or response between women and men in the FOI group (68% vs. 70.5%; odds ratio: 1.12; p = 0.82; 95% CI: 0.41 to 3.07). FOI extended the atrioventricular interval to obtain the best fusion; the atrioventricular intervals tended to require greater extension in men than in women (22 ± 33 ms vs. 8 ± 28 ms, respectively; p = 0.07)., Conclusions: Women had a shorter PR interval, which was associated with a shorter QRS interval and better response to CRT. The difference in QRS interval duration and response between men and women did not persist when CRT was optimized using fusion with intrinsic conduction (FOI programming)., Competing Interests: Funding Support and Author Disclosures Dr. Pujol-López is funded by the Research Grant Josep Font 2019, Hospital Clínic de Barcelona. Dr. San Antonio is funded by a Jordi Soler Training Grant, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares 2018. Dr. Tolosana has received honoraria as a lecturer and consultant for Abbott, Boston Scientific, and Medtronic. Dr. Roca has received honoraria as a lecturer and consultant for Abbott and Biosense Webster. Dr. Varma has received honoraria as a lecturer and consultant for Abbott, Biotronik, Boston Scientific, EP Solutions, Medtronic, and Microport. Dr. Mont has received unrestricted research grants, fellowship program support, and honoraria as a lecturer and consultant from Abbott, Biotronik, Boston Scientific, Livanova, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)