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Background: Our previous study reported that histamine H2 receptor antagonists (H2RAs) exposure was associated with decreased mortality in critically ill patients with heart failure (HF) through the same pharmacological mechanism as β-blockers. However, population-based clinical study directly comparing the efficacy of H2RAs and β-blockers on mortality of HF patients are still lacking. This study aims to compare the association difference of H2RAs and β-blockers on mortality in critically ill patients with HF using the Medical Information Mart for Intensive Care III database (MIMIC-III).Methods: Study population was divided into 4 groups: β-blockers + H2RAs group, β-blockers group, H2RAs group, and Non-β-blockers + Non-H2RAs group. Kaplan–Meier curves and multivariable Cox regression models were employed to evaluate the differences of all-cause mortalities among the 4 groups. Propensity score matching (PSM) was used to increase comparability of four groups.Results: A total of 5593 patients were included. After PSM, multivariate analyses showed that patients in H2RAs group had close all-cause mortality with patients in β-blockers group. Furthermore, 30-day, 1-year, 5-year and 10-year all-mortality of patients in β-blockers + H2RAs group were significantly lower than those of patients in β-blockers group, respectively (HR: 0.64, 95%CI: 0.50–0.82 for 30-day; HR: 0.80, 95%CI: 0.69–0.93 for 1-year mortality; HR: 0.83, 95%CI: 0.74–0.93 for 5-year mortality; and HR: 0.85, 95%CI: 0.76–0.94 for 10-year mortality, respectively).Conclusion: H2RAs exposure exhibited comparable all-cause mortality-decreasing effect as β-blockers; and, furthermore, H2RAs and β-blockers had additive or synergistic interactions to improve survival in critically ill patients with HF.