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Abstract Background: Patients with sickle cell disease (SCD) often experience recurrent hospitalizations due to both acute complications and chronic comorbidities, resulting in frequent exposure to antibiotics and healthcare settings, which are key risk factors for Clostridium difficile infection (CDI). Although CDI is well studied in the general population, its epidemiology, risk factors, and clinical impact in patients with SCD remain poorly defined on a national level. Methods: We utilized the National Inpatient Sample (NIS) database from 2016-2022 to identify patients with a diagnosis of SCD using ICD-10 codes. Among them, patients with CDI were identified. We compared demographic, clinical, and hospital-level characteristics between SCD patients with and without CDI. Multivariable logistic regression was used to assess independent predictors of CDI and its association with acute complications. Temporal trends in CDI prevalence were evaluated using regression models. Results: Among 177,814 SCD-related hospitalizations, 661 involved CDI, corresponding to a CDI rate of 3.7 per 1000 SCD hospitalizations, lower than the estimated 8–10 per 1000 admissions calculated from general population data. The prevalence of CDI decreased from 5.5 per 1000 in 2016 to 2.7 per 1000 in 2022 (p for linear trend < 0.001), reflecting an average annual decline of 6.9% (OR per year: 0.931; 95% CI: 0.909–0.953; p < 0.001). Patients with CDI were older (mean age 37.9 vs. 30.1 years, p<0.001), more likely to be female (62.0% vs. 55.7%, p=0.001), and had a higher proportion of White patients (3.5% vs. 1.7%, p=0.002). A greater proportion of patients with CDI had higher comorbidity burden (CCI ≥3: 26.0% vs. 8.8%, p<0.001). They also had significantly longer hospital stays (11.96 ± 17.09 vs. 5.19 ± 6.13 days, p<0.001) and higher total hospital charges ($141,817 ± $295,844 vs. $46,008 ± $87,142, p<0.001). The strongest independent predictors of CDI included inflammatory bowel disease (aOR 7.65, 95% CI: 4.86–12.06, p<0.001), history of hematopoietic stem cell transplant (aOR 6.55, 95% CI: 3.80–11.31, p<0.001), and HIV (aOR 2.13, 95% CI: 1.28–3.55, p=0.004). Other significant predictors included increasing age (aOR 1.02, 95% CI: 1.01–1.02, p<0.001), female sex (aOR 1.22, 95% CI: 1.03–1.45, p=0.022), CKD (aOR 1.60, 95% CI: 1.27–2.03, p<0.001), diabetes mellitus (aOR 1.74, 95% CI: 1.35–2.22, p<0.001), cirrhosis (aOR 1.95, 95% CI: 1.30–2.91, p=0.001), and congestive heart failure (aOR 1.35, 95% CI: 1.05–1.74, p=0.019). Insurance type, hospital region, location, and obesity were not significantly associated with CDI after adjustment. In adjusted multivariate analyses, CDI was associated with significantly increased odds of several acute complications of SCD. These included sepsis (aOR 3.56, 95% CI: 2.88–4.40, p<0.001), acute osteomyelitis (aOR 2.38, 95% CI: 1.26–4.47, p=0.007), deep vein thrombosis (aOR 2.19, 95% CI: 1.58–3.04, p<0.001), acute kidney injury (aOR 2.14, 95% CI: 1.71–2.68, p<0.001), pulmonary embolism (aOR 2.13, 95% CI: 1.34–3.38, p=0.001), pneumonia (aOR 1.85, 95% CI: 1.12–3.06, p=0.016), and acute respiratory failure (aOR 1.60, 95% CI: 1.22–2.07, p<0.001). CDI was not associated with increased odds of acute chest syndrome, stroke, splenic sequestration, kidney infarction, acute myocardial infarction or in-hospital mortality. Conclusions: The incidence of CDI was less common in hospitalized patients with SCD than in the general population. CDI was associated with classical infectious and thrombotic complications (e.g., pneumonia, osteomyelitis, sepsis, DVT, PE), but not with SCD-specific vaso-occlusive events such as acute chest syndrome, stroke, splenic sequestration, or kidney infarction. Notably, our study demonstrates a decreasing trend in CDI prevalence among SCD hospitalizations from 2016 to 2022, contrasting with prior national data that reported rising rates. Nevertheless, CDI is associated with significantly increased healthcare utilization and length of stay, perhaps because the predictors of CDI in this population such as immunosuppression and chronic comorbidities are consistent with known risk factors in the general inpatient population.