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Background: SCD poses a significant healthcare burden. Understanding the factors contributing to high healthcare utilization and readmissions is crucial for improving the quality of care provided. Methods: This retrospective comparative observational study was conducted at King Saud University Medical City and included 160 SCD patients. A comparison was made between patients with no readmission and patients with at least one 30-day readmission. Another comparison was done between high healthcare-utilizing patients and low healthcare-utilizing patients. A regression model for 30-day readmission prediction was created. Results: Readmission was significantly higher in patients using opioids, following up with pain clinics, and having a history of AVN (p= 0.002, p=0.028 and p=0.025 respectively). Higher healthcare utilization was associated with older age, smoking, use of opioids and GABA analogs, and psychiatric illnesses, including depression, substance use disorder, and anxiety. Predictors of 30-day readmission were hydroxyurea use (odds ratio, 2.819 [95% CI,1.082 to 7.34], p = 0.034), follow-up with pain management clinics (odds ratio, 2.248 [95% CI,1.547 to 3.266], p = 0.001), and SCD genotype (SS genotype) (odds ratio, 1.754 [95% CI,1.012 to 3.042], p = 0.045). Using the Paracetamol/Codeine combination significantly reduced the likelihood of readmission within 30 days of discharge. Conclusion: This study identified factors associated with 30-day readmission rate and high healthcare utilization among SCD patients. Strategies to reduce readmissions may include specialized SCD clinics, educational programs for patients, improved physician awareness of mental health screening, and further research on the impact of opioid use. Limitations include retrospective nature, single-center design, reliance on self-reported data, and exclusion of critically ill patients. However, despite the limitations, this study could lay a foundation for future projects aiming to optimize care and outcomes for patients living with SCD. [ABSTRACT FROM AUTHOR]