The model of local control of oxygen delivery in the microvasculature developed by H. J. Granger and A. P. Shepherd (1973, Microvasc. Res. 5, 49-72) was extended to describe microcirculatory blood flow in sickle cell disease. Two major characteristics of sickle cell blood were incorporated into the model: an abnormal blood viscosity which is dependent on the degree of hemoglobin oxygen saturation and hematocrit, and a reduced affinity of hemoglobin (Hb) for oxygen. Sickle cell blood viscosity as a function of oxygen saturation and hematocrit was modeled empirically based upon existing data. Alterations in HbO2 affinity were studied in the model by introducing P50 as an independent variable. The altered oxygen supply/demand relationship in sickle cell disease was simulated following an increase in tissue metabolic demand and a decrease in arteriolar blood flow. The results were analyzed to evaluate the roles of the various rheological characteristics of sickle cell blood in affecting microcirculatory dynamics and tissue oxygen delivery. It was demonstrated that, within the hematocrit range of 20 to 45%, the elevation of P50 from 27 to 38 mm Hg in sickle cell blood is adequate to compensate for the diminished O2 content, despite an elevated blood viscosity, and maintain near normal tissue pO2.