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Background Cardiac remodeling and its reversibility are key in HF outcomes. The ST2-R2 score was recently developed to predict relevant left ventricular (LV) reverse remodeling (R2) in patients with heart failure (HF). In the present study we sought to validate the ST2-R2 score for grading improvement in LV ejection fraction (EF) and LV size at one year, and to evaluate its prognostic implication up to 4 years. Methods A total of 569 patients with baseline LVEF < 40% from three international cohorts (Barcelona, TIME-CHF, and PROTECT) were included in the study. Patients were classified into four strata based on their ST2-R2 score, which took into account concentrations of the biomarker ST2, non-ischemic etiology, absence of left bundle branch block, HF duration, baseline LVEF, and β-blocker treatment. Results A significant relationship was observed between ST2-R2 scores and changes in LVEF and indexed LV sizes. LVEF recovery (from + 5.6% to + 17.3%; p < 0.001), percentage reduction in LV end-systolic volume index (from − 6.1% to − 32.1%; p < 0.001) and in LV end-systolic diameter index (from − 1.1% to − 18.6%; p < 0.001) increased over the ST2-R2 strata. A similar trend was observed with diastolic parameters. Improvement in LV function and size was inversely predictive of mortality. Hazard ratios for risk of death, using the lower ST2-R2 score strata (< 9) as a reference, were 0.49 (p < 0.001; score 9–11), 0.27 (p < 0.001; score 12–14), and 0.17 (p < 0.001; score 15–17). Conclusions The ST2-R2 score predicts reverse LV remodeling in HF patients and is useful for predicting mortality up to 4 years. [ABSTRACT FROM AUTHOR]