BACKGROUND: Galectin-3 predicts prognosis in heart failure (HF) and may help to select HF patients in need of intensified therapy. METHODS: This retrospective post hoc analysis included 219 patients from the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-HF) and 631 patients from Gruppo Italiano perlo Studio della Soprawivenza nell'Insufficienza Cardiaca (GISSI-HF) with HF who had reduced ejection fraction and available galectin-3 plasma concentrations. The interaction between galectin-3, beta-blockers, renin-angiotensin system (RAS) blockade, and spironolactone on outcome was evaluated in TIME-CHF and validated in GISSI-HF. End points were all-cause mortality and the composite of mortality with HF hospitalization or any hospitalization. RESULTS: High galectin-3 concentrations were associated with adverse outcome in both cohorts and remained significantly associated with death after multivariate adjustment [hazard ratio 2.42 (95% CI 1.17-5.01), P = 0.02, in TIME-CHF; 1.47 (1.02-2.10), P = 0.04, in GISSI-HF). In TIME-CHF, patients with low galectin-3 plasma concentrations had a better prognosis when beta-blockers were up-titrated, whereas patients with high galectin-3 plasma concentrations did not (interaction P <0.05 for mortality and death with or without hospitalization). Opposite trends were seen for RAS blockade but were not statistically significant. Patients with high galectin-3 plasma concentrations had neutral prognosis when receiving spironolactone, whereas patients with low galectin-3 plasma concentrations had worse prognosis when receiving spironolactone (interaction P <0.10 for death with or without hospitalization). In the GISSI-HF validation cohort, these interactions were confirmed for beta-blockers (P <0.05 for all end points) and consistent for RAS blockade (P <0.10 for death with or without hospitalization), but inconsistent for spironolactone. CONCLUSIONS: Galectin-3 is a mediocre prognostic marker, and galectin-3 concentrations interact with the treatment effect of beta-blockers and possibly RAS blockade in patients with systolic HF.