Background: Simple chronic transfusion therapy (CTT) is a mainstay for stroke prophylaxis in sickle cell anemia, but its effects on hemodynamics are poorly characterized. Transfusion improves oxygen-carrying capacity, reducing demands for high cardiac output. While transfusion decreases factors associated with vasoocclusion, including percent hemoglobin (Hb)S, reticulocyte count, and circulating cell-free Hb, it increases blood viscosity, which reduces microvascular flow. The hematocrit-to-viscosity ratio (HVR) is an index of red blood cell oxygen transport effectiveness that varies with shear stress and balances the benefits of improved oxygen capacity to viscosity-mediated impairment of microvascular flow. We hypothesized that transfusion would improve HVR at high shear despite increased blood viscosity, but would decrease HVR at low shear. STUDY DESIGN AND METHODS: To test this hypothesis, we examined oxygenated and deoxygenated blood samples from 15 sickle cell patients on CTT immediately before transfusion and again 12 to 120 hours after transfusion. Results: Comparable changes in Hb, hematocrit (Hct), reticulocyte count, and HbS with transfusion were observed in all subjects. Viscosity, Hct, and high-shear HVR increased with transfusion while low-shear HVR decreased significantly. CONCLUSION: Decreased low-shear HVR suggests impaired oxygen transport to low-flow regions and may explain why some complications of sickle cell anemia are ameliorated by CTT and others may be made worse.