Background: Both men and women have a comparable overall lifetime chance of developing heart failure, but there are clear sex differences in the nature of this condition that are both significant and yet underexplored. In this study, we investigate gender differences in clinical characteristics and in-hospital outcomes of heart failure hospitalizations using a large national database. Methods: This study is a retrospective analysis of National Inpatient Sample data, 2016-2019. Hospitalizations ≥41 years of age, admitted for heart failure were included in the study and stratified by sex. The outcomes of the study were in-hospital mortality rate, prolonged hospital length of stay, mechanical ventilation, mechanical circulatory support, vasopressors use, and adverse disposition. Propensity score matching with conditional logistic regression analysis was done to compare outcomes between males and females. Results: A total of 4,704,684 primary heart failure hospitalizations were included for the analysis. Of these 2,447,784 (52.0%) were males and 2,256,899 (48.0%) were females. In-hospital mortality ( P <0.001), mechanical ventilation ( P <0.001), mechanical circulatory support ( P <0.001), and vasopressors use ( P <0.001) were significantly lower among females, while prolonged length of stay ( P <0.001) and disposition other than home ( P <0.001) were higher among females. Conditional logistics regression analysis showed that females had significantly lower odds for mortality (aOR, 0.92, 95% CI: 0.89-0.94), mechanical ventilation (aOR, 0.89, 95% CI: 0.86-0.92), mechanical circulatory support (aOR, 0.54, 95% CI: 0.50-0.58), vasopressor use (aOR, 0.70, 95% CI: 0.66-0.74), and significantly higher odds for prolonged length of stay (aOR, 1.05, 95% CI: 1.04-1.06) and disposition other than home (aOR, 1.32, 95% CI: 1.31-1.34) Conclusion: Results of our study show that there are significant differences in outcomes between males and females hospitalized for heart failure. Further research is required to delineate how sex affects several aspects of heart failure, including epidemiology, risk factors, pathogenesis, response to medication, and eventually outcomes.