Mineralocorticoid receptor antagonists (MRAs) are recommended as part of guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF). The comparative effectiveness of spironolactone and eplerenone, however, remains uncertain. This was a non-interventional database study using nationwide Danish health registries, January 1, 2020-June 30, 2025. Patients aged ≥45 years with HFrEF (ejection fraction ≤40%) initiating eplerenone or spironolactone were included. An active-comparator, new-user design and inverse-probability-of-treatment weighting based on propensity scores was used. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, heart failure hospitalization, and their composite. Weighted hazard ratios (wHRs) were estimated using Cox proportional hazards models.A total of 4550 patients initiating eplerenone and 6651 initiating spironolactone were included. Median follow-up was 2.3 years. There were 571 deaths in the eplerenone group (5.0 per 100 person-years) and 1168 in the spironolactone group (7.0 per 100 person-years). A lower risk of death was observed with eplerenone (wHR, 0.83; 95% CI, 0.75-0.93), corresponding to an absolute rate difference of -1.10 per 100 person-years (95% CI, -0.50 to -1.70). For secondary outcomes, wHRs were 0.89 (95% CI, 0.81-0.98) for cardiovascular death or heart failure hospitalization, 0.79 (95% CI, 0.67-0.92) for cardiovascular death, and 0.97 (95% CI, 0.87-1.09) for heart failure hospitalization.Effect estimates were attenuated in per-protocol analyses. In this large nationwide study, initiation of eplerenone was associated with lower risks of all-cause and cardiovascular mortality compared with spironolactone, with findings suggesting a contribution of better treatment persistence.