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Introduction: Sickle cell disease (SCD) is a genetic disorder that is widely observed on a global scale and known for its substantial negative impact on health and mortality. The purpose of this research was to explore how SCD influences the outcomes of acute coronary syndrome (ACS) and Percutaneous Coronary Intervention (PCI). Methods: A retrospective observational analysis was conducted using the National Inpatient Sample (NIS) data for the year 2020. Adult patients with concurrent ACS and SCD diagnoses were included in the study. Demographic information, clinical characteristics, in-hospital outcomes, and PCI complications were examined and compared between ACS patients with and without SCD. Results: Among a total of 779,895 ACS patients, 1495 had coexisting SCD. SCD patiets exhibited distinct demographic features, such as younger age (mean age: 59 vs. 66 years), predominantly female (53% vs. 35%), and primarily African American (91% vs. 11%). Comorbid conditions such as hypertension and chronic lung disease were more prevalent in SCD patients. While inpatient mortality odds did not significantly differ, SCD patients demonstrated slightly shorter lengths of stay in cases of STEMI and NSTEMI/UA. Notably, SCD patients faced a statistically significant increased risk of coronary dissection, highlighting a unique complication in this population. Although an increased incidence of atrial fibrillation and acute heart failure was observed in SCD patients, statistical significance was not achieved. Conclusions: This study provides valuable insight into the intricate interplay between SCD and ACS outcomes. SCD patients presented with distinctive demographic and clinical profiles that influenced their experience with ACS. The elevated risk of coronary dissection emphasizes the necessity for tailored interventions and careful management in SCD patients. These findings underscore the need for further research to elucidate underlying mechanisms and optimize treatment strategies for individuals with both SCD and ACS.