ObjectiveThe present study compares postoperative outcomes between patients with and without sickle cell disease (SCD) undergoing one- to three-level lumbar spinal fusion for degenerative pathologies. MethodsPatients who underwent one- to three-level lumbar spinal fusion for degenerative pathologies from 2010–2021 were identified using the PearlDiver database. Patients were separated into 1) SCD and 2) non-SCD groups and were propensity-matched 1:1 for age, sex, Elixhauser Comorbidity Index (ECI), surgical approach, and various comorbidities. Complications were separately analyzed by single- and multi-level procedures using chi-squared and Mann-Whitney U testing. ResultsPropensity-score matching identified 1,934 SCD and non-SCD patients who underwent single-level fusion and 2,094 SCD and non-SCD patients who underwent multi-level fusion. Across single-level fusions, those with SCD had a significantly higher risk of neurovascular compromise (p < 0.001), venous thromboembolism (p = 0.004), pneumonia (p = 0.032), urinary tract infections (UTI) (p = 0.001), and greater postoperative opioid usage out to twelve months (p = 0.018). Across multi-level fusions, SCD carried higher risk for neurovascular compromise (p < 0.001), pneumonia (p = 0.010), and UTI (p < 0.001). All SCD patients had significantly higher opioid use at one month (p = 0.001) and at six months (p = 0.009) postoperatively. ConclusionsPatients with SCD undergoing lumbar spinal fusion demonstrate higher risks for coagulopathic, ischemic, and infectious-related complications, as well as long-term postoperative opioid use. Awareness of the unique complication profile in SCD patients may help guide surgeons in refining perioperative management strategies to optimize outcomes in patients with SCD.