Abstract Background and Purpose Tachycardiomyopathy (TCM) is prevalent in heart failure with reduced ejection fraction (HFrEF). Despite its significance, a comprehensive understanding of its evolutionary trajectory and prognosis remains limited. This study aims to investigate the prognosis and left ventricular ejection fraction (LVEF) trajectory in patients with TCM compared to other etiologies within a cohort initially admitted for "de novo" HFrEF (LVEF < 40%). Methods A prospective registry was conducted across two University Hospitals, incorporating patients hospitalized with a diagnosis of HFrEF. The study encompassed 370 patients admitted between March 2021 and October 2023, with a median follow-up of 15 months (IQR 7-22). Two distinct groups were delineated based on etiology (TCM vs other etiologies). Within the TCM cohort, subgroups were established concerning LVEF improvement, following the criteria outlined in the "Universal Definition and Classification of Heart Failure" report. Categorical variables were presented as absolute frequencies and percentages, analyzed using the chi-square test. Continuous variables were expressed as mean +/- SD and compared through Student's t-test or Mann-Whitney U test. Hazard functions were estimated using the Kaplan-Meier method. Data analysis was executed using SPSS Statistics. Results In our cohort, both TCM and other etiologies groups exhibited improved LVEF post-neurohumoral blockage titration. Nonetheless, the TCM cohort demonstrated notably higher LVEF (49.1% vs. 43.5%, p = 0.005) [Figure 1]. Moreover, overall mortality, cardiovascular mortality, and the composite of CV mortality and hospitalizations for CV causes were notably lower in the TCM group compared to other etiologies [Figure 2]. Among TCM patients, those with improved LVEF during follow-up were younger (66 vs. 72), with no differences in treatment at discharge or after neurohumoral blockage titration. While achieving sinus rhythm before discharge did not correlate with LVEF improvement, attaining sinus rhythm during follow-up (at titration completion) significantly correlated with LVEF improvement [Table 1]. Multivariate analysis revealed that sinus rhythm restoration after up-titration emerged as an independent predictor of LVEF improvement, irrespective of sinus rhythm restoration at discharge or the attainment of quadruple therapy during follow-up, among other variables (Table 2). Conclusions Among patients initially admitted for "de novo" HFrEF, TCM presents a potentially more favorable clinical trajectory compared to other HF causes, showcasing reduced total and cardiovascular mortality, as well as combined cardiovascular mortality and hospitalizations for cardiovascular causes. Notably, in this patient subset, sinus rhythm restoration during follow-up emerged as an independent predictor of improved LVEF, irrespective of pre-discharge sinus rhythm restoration or adherence to comprehensive four-pillar HF management.