Background: Sickle cell disease (SCD) is a genetic blood disorder that results in vaso-occlusive events and shortened lifespan. Medical advancements have led to a decrease in childhood mortality in SCD, but the transition period is associated with poor outcomes. We analyzed recent US hospitalizations and mortality trends in the transition-aged population and evaluated for differences between patients with and without SCD. Methods: Nationwide Impatient Sample (NIS) database was utilized to analyze hospitalizations among individuals aged 16-24 years from 2003-2017. Diagnoses were coded using ICD-9-CM and ICD-10-CM. Statistical analyses included: bivariate analyses to assess the association between socio-demographic characteristics, joinpoint regression analysis to describe trends in mortality rates, average annual percent change (AAPC) measures were calculated, and adjusted survey logistic regression to assess the association between patient characteristics and in-hospital mortality. Results: Our data captured 37,344,532 total patients between the age of 16 and 24 who were hospitalized during 2003-2017. Patients with SCD comprised of 1.20% of population with a significant +3.2% AAPC in hospitalizations. When comparing SCD to non-SCD hospitalization trends, we observed differences in gender, against-medical-advice discharge status, zip code income, and payer. SCD in-hospital mortality rates showed a non-significant -0.7% AAPC. However, in contrast to non-SCD patients, the odds ratios for in-hospital mortality significantly increased with age for SCD patients. Conclusion: During the transition period, SCD patients have an extremely increased likelihood of mortality. Proposed interventions to address this disparity must include targeting social determinants of health.