OBJECTIVE To establish reference values of the ratios of flow velocity in the middle cerebral artery (V(MCA)) and the terminal portion of the internal carotid artery (V(tICA)) to flow velocity in the extracranial portion of internal carotid artery (V(ICA)) in children with sickle cell disease (SCD). METHODS Institutional ethics committee approval and parental informed consent were obtained for this prospective HIPAA-compliant study. Sixty-eight children (38 female; mean age, 7.7 years +/- 3.3; range, 2-14 years) with HbSS genotype, without neurologic deficits and no history of stroke, were enrolled. Final study population comprised 56 (mean age 8.0 +/- 3.3 years, 26 females) children who underwent magnetic resonance (MR) angiography, which excluded intracranial arterial narrowing, transcranial color-coded duplex ultrasonography (US), and carotid US to determine V(MCA)/V(ICA) and V(tICA)/V(ICA) ratios from angle-corrected and uncorrected velocities. Tolerance interval estimates were used to calculate reference ranges and linear regression was used to quantify associations of Doppler parameters with age adjusted for hemoglobin and hematocrit. RESULTS Reference ranges in centimeters per second for mean angle-corrected V(MCA) on the left and right sides were 62-198 and 69-153; those for V(tICA) were 30-196 and 36-175; and those for V(ICA) were 18-116 and 15-95, respectively. Reference ranges for mean angle-corrected V(MCA)/V(ICA) ratio on the left and right sides were 1.2-4.0 and 0.4-3.4 and those for V(tICA)/V(IC)(A) ratio were 0.5-2.9 and 0.5-2.7, respectively. V(MCA), V(tICA), and V(tICA)/V(ICA) ratio were not age dependent, contrary to V(ICA) and V(MCA)/V(ICA) ratio, after controlling for hematocrit and hemoglobin. CONCLUSIONS The study provides reference limits for V(MCA), V(tICA), V(ICA), and velocity ratios obtained from children with SCD.