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Left bundle branch block (LBBB)-induced cardiomyopathy occurs in patients with long-standing LBBB. These patients characteristically exhibit hyperresponsiveness to cardiac resynchronization therapies (CRT). However, there is scarce information on their response to medical treatment. The aim of this study was to assess the change in left ventricular ejection fraction (LVEF) after a 3-month period following titration of guideline-directed medical therapy for heart failure.This retrospective analysis included all patients assessed in the heart failure unit of a Spanish University Hospital between 2020 and 2021, who presented with de novo ventricular dysfunction (LVEF40%) and had a history of long-standing LBBB with no other possible causes of cardiomyopathy.A total of 1497 patients were analyzed, of which 21 were finally eligible. Mean time from first diagnosis of LBBB to first consultation was 4.05± 4.1 years. Mean LVEF from first consultation to end of titration improved from 29.5±5.7% to 32.7±8.6% (P = .172), but none had recovered ventricular function at the end of follow-up. New York Heart Association functional class improved from 1.91±0.46 to 1.81±0.53 (P=.542). After CRT device implantation in 8 patients, LVEF improved by 14.5±3.5% (P=.003).Guideline-directed medical therapy seems to be ineffective in improving LVEF and functional class in patients with de novo heart failure and LBBB-induced cardiomyopathy. Based on a positive response to CRT on LVEF improvement, early CRT implantation could be a reasonable strategy for these patients.