Sickle cell disease (SCD) accounts for~ 100,000 hospitalizations in the US annually. Quality of care for hospitalized SCD patients has been insufficiently studied. Therefore, we aimed to examine whether four potential determinants of quality care,[1] hospital volume,[2] hospital teaching status,[3] patient socioeconomic status (SES), and [4] patient insurance status are associated with three quality indicators for patients with SCD:[1] mortality,[2] length of stay (LOS), and [3] hospitalization costs. We conducted an analysis of the 2003–2005 Nationwide Inpatient Sample (NIS) datasets. We identified cases using all ICD-9CM codes for SCD. Both overall and SCD-specific hospital volumes were examined. Multivariable analyses included mixed linear models to examine LOS and costs, and logistic regression to examine mortality. About 71,481 SCD discharges occurred from 2003 to 2005. Four hundred and twenty five patients died, yielding a mortality rate of 0.6%. Multivariable analyses revealed that SCD patients admitted to lower SCD-specific volume hospitals had [1] increased adjusted odds of mortality (quintiles 1–4 vs. quintile 5: OR, 1.36; 95% CI, 1.05, 1.76) and [2] decreased LOS (quintiles 1–4 vs. quintile 5, effect estimate− 0.08; 95% CI,− 0.12,− 0.04). These are the first data describing associations between lower SCD-specific hospital volumes and poorer outcomes.