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Sickle cell disease (SCD) is the most common inheritable hematologic disorder in the USA and is associated with ischemic organ diseases. SCD-associated ischemic bowel disease is increasing being recognized, and studies on the hospitalization outcomes of such patients are limited.This study aimed to compare the inpatient outcomes of ischemic bowel disease among patients with SCD compared with patients without SCD.This is a case–control study using data from the National Inpatient Sample Database (2007–2014). We analyzed and compared outcomes between cases (ischemic bowel disease with SCD) and controls (ischemic bowel disease without SCD), matched in a 1 : 5 ratio. The primary outcome was in-hospital mortality, and the secondary outcomes were healthcare resource utilization including mechanical ventilation, hemodialysis, transfusion, length of stay, and hospital charges.Of the 194 262 patients admitted with ischemic bowel disease, 98 had a diagnosis of SCD and were matched successfully to the controls. In multivariate analysis, patients with SCD had twice the mortality odds of those without (adjusted odds ratio=2.06, 95% confidence intervals: 1.13–3.74). They were more likely to require mechanical ventilation and blood transfusion, and to be discharged to secondary health facilities [1.68 (1.02–2.76), 3.32 (2.15–5.12), and 1.84 (1.02–3.35)]. Patients with SCD also had a higher frequency of pneumonia, acute respiratory failure, and hemodialysis for acute renal failure. There was no significant difference in the length of stay or the total hospital charge between the two groups.In patients hospitalized with ischemic bowel disease, SCD is associated with significantly increased mortality and healthcare burden.