The degree of fetal hemoglobin (HbF) expression is a major determinant of phenotypic severity of sickle cell disease (SCD). Genetic regulation of HbF production is complex and can vary among ethnic groups. The pediatric sickle cell population at our institution is approximately half Hispanic, nearly all from the Dominican Republic. Hydroxyurea (HU) is the only Food and Drug Administration (FDA)-approved drug to ameliorate symptoms of SCD. We retrospectively compared baseline and HU-induced percent HbF (%HbF) in African American (AA) and Hispanic (H) patients aged 4 to 21 years with homozygous Sickle hemoglobin or HbSβ(0)Thalassemia. No significant differences were detected in average baseline %HbF between AA (N=48) and H (N=58) patients (P=0.63). In the subset of children taking HU who reached maximum tolerated dose (MTD), no differences were found between the ethnic groups in laboratory response to drug, measured by %HbF at MTD (P=0.28), the increase in %HbF (P=0.31) or mean red cell volume (MCV) (P=0.93), or the MTD of HU (P=0.95). Regulation of HbF at baseline and in response to HU are comparable between Hispanics and African Americans at our center. If generalizable, our results support combining these 2 groups in future clinical and translational analyses focused on HbF and response to HU in this ethnically mixed patient population.