Introduction: Acute coronary syndrome (ACS) is a leading cause of cardiovascular (CV) death. Sickle cell disease (SCD) is the most common inherited blood disorder in the United States and is associated with coronary microvascular dysfunction and impaired myocardial perfusion reserve. However, data on post-ACS outcomes in patients with SCD are scarce.Methods: Patients admitted with ACS from 2014-2020 with and without SCD were identified using the National Readmissions Database. In-hospital outcomes were death, major bleeding, stroke or arterial thromboembolism, and venous thromboembolism (VTE). Ninety-day readmission outcomes were CV-related, heart failure (HF) related, bleeding-related, and all-cause. Multivariable logistic or Cox proportional hazards were utilized with age, sex, chronic kidney disease, prior MI, prior stroke, prior VTE, pulmonary hypertension, STEMI, cardiogenic shock, revascularization, anemia, mechanical circulatory support use, hospital size and teaching status in addition to social factors as co-variables.Results: A total of 2,190,358 patients with ACS were included, of whom 1,471 (0.067%) had SCD. After multivariable adjustment, there was no difference in in-hospital mortality (OR 0.92; 95% CI 0.68-1.26) or major bleeding (OR 1.03; 95% CI 0.82-1.28) between patients with and without SCD. There was no significant difference in 90-day CV-related (HR 1.11; 95% CI 0.94-1.3) or bleeding-related (HR 0.86; 95% CI 0.49-1.52) readmissions between patients with and without SCD. However, SCD was associated with a higher rate of HF-related (HR 1.25; 95% CI, 1.04-1.52) and all-cause 90-day readmissions (HR 1.17; 95% CI, 1.04-1.32).Conclusion: Among patients admitted with ACS, SCD was not associated with increased risk of in-hospital outcomes though there was an association of increased HF-related and all-cause 90-day readmissions with SCD. Further investigation is needed to better characterize and improve outcomes of patients with SCD and ACS.