Abstract Background Systemic lupus erythematosus (SLE) is known to have an impact on cardiovascular outcomes, but its effect on patients with acute decompensated heart failure (ADHF) with reduced and preserved ejection fraction is not well understood. This study aims to investigate the impact of SLE on in-hospital outcomes in patients with ADHF. Methods This retrospective cohort study analyzed data from the United States National Inpatient Sample Database from 2016 to 2020. Patients hospitalized with ADHF with reduced and preserved ejection fraction were identified using ICD-10 codes and then categorized based on SLE diagnosis. Mortality and in-hospital complications were analyzed using multivariate logistic regression. Results Out of 10,700,000 ADHF hospitalizations, 0.61% (65,270) were associated with SLE. Compared to patients without SLE, those with SLE were younger (61 vs 72 years old, p<0.001), more likely to be female (85% vs 48%, p<0.001), had longer lengths of stay (coefficient: 0.23; p 0.005), and lower total hospital charges (coefficient: -$5,207; p<0.001). Patients with SLE had lower rates of cardiogenic shock, acute MI, and ischemic stroke (Figure 1). However, they had higher odds of in-hospital mortality, gastrointestinal bleeding, blood transfusion, pericardial complications, and AKI. No significant differences were found in respiratory failure and intracranial hemorrhage rates between the two cohorts. Conclusions This study suggests that the presence of SLE in patients hospitalized with ADHF is associated with worse in-hospital outcomes, including higher rates of all-cause mortality, gastrointestinal bleeding, blood transfusion, pericardial complications, and AKI. However, patients with SLE had lower rates of cardiogenic shock, acute MI, and ischemic stroke compared to those without SLE. These findings highlight the importance of early recognition and aggressive management of SLE in patients with ADHF to improve outcomes. Further research is needed to identify potential interventions that could improve the outcomes of this high-risk population.