Background Patients with heart failure with reduced ejection fraction (HFrEF) who achieve reverse remodelling (RR) can experience a new decrease in ejection fraction (EF), and the predictors of sustained RR (SRR) are not completely understood. Objectives The study aims to identify predictors of SRR in patients with HFrEF after an increase in EF and evaluate SRR prognosis. Methods In this retrospective, observational study, we evaluated a real-life cohort of patients with HFrEF and >= 2 consecutive echocardiograms, divided according to left ventricular EF (LVEF) trajectory: no RR (NRR: 3/3 LVEF measurements < 40%), non-SRR (NSRR: second LVEF >= 40%, third LVEF < 40%), and SRR (SRR: second and third LVEF >= 40%). Results We included 3628 of 8072 assessed HF patients in the analysis, with mean age 56.2 (+/- 13.4) years, 64.4% male and 77.7% New York Heart Association (NYHA) I-II. Improved EF was observed for 1342 (37%) patients. Among those who achieved RR, 310 (23%) were NSRR, and 1032 (77%) were SRR. The mean (+/- SE) survival after the second echocardiogram was 10.6 (+/- 0.2) years. The SRR group had the longest survival (12.2 +/- 0.3 years), followed by the NSRR (10.6 +/- 0.5) and NRR (9.8 +/- 0.2 years) groups (P < 0.001). According to logistic multivariable regression, second LVEF [odds ratio (OR) = 1.06, confidence interval (CI) = 1.03-1.90, P < 0.001], second left ventricular end-systolic diameter (LVESD) (OR = 0.93, CI = 0.90-0.96, P < 0.001), second IV septum thickness (OR = 1.12, CI = 1.03-1.23, P = 0.012), systolic blood pressure (OR = 1.01, CI = 1.00-1.02, P = 0.014), NYHA I-II (OR = 1.86, CI = 1.27-2.74, P = 0.001) and furosemide non-use (OR = 1.87, CI = 1.27-2.74, P < 0.001) independently predicted SRR. Conclusions Patients with greater EF increases and LVESD reductions at EF recovery, greater septum thickness, higher blood pressure, no need for diuretics and NYHA I/II maintenance had the best chance of maintaining recovered ventricular function.