BACKGROUND: Guidelines for transfusion in sickle cell disease usually define an upper hematocrit (Hct) limit of 0.30 to 0.35 to avoid blood hyperviscosity. In vitro viscosity studies of normal (AA) and sickle (SS) red blood cell (RBC) mixtures in buffer appear to confirm that this Hct limit is optimal for oxygen delivery to vascular beds as judged by the ratio of Hct to viscosity, with this ratio often termed "oxygen or RBC transport effectiveness." In the absence of plasma, however, effects due to RBC-RBC interactions mediated by plasma proteins cannot be assessed. STUDY DESIGNS AND METHODS: To investigate the optimal Hct-to-viscosity ratio of RBCs in plasma, the rheologic effects of Hct (0.20-0.40), the proportion of SS RBCs (0-100%), and shear rate (1-1000/sec) for mixtures of oxygenated and deoxygenated SS and AA RBCs were evaluated in sickle plasma at 37°C. RESULTS: RBC suspension viscosity was shear-dependent (i.e., viscosity decreased with increasing shear rate) and increased with Hct and proportion of SS RBCs. An "optimal" Hct level (defined as a maximal of the Hct-to-viscosity ratio) was seen only at shear rates above 50/sec. At lower shear rates (e.g., 5/sec), where plasma-mediated RBC-RBC interactions predominate, any increment in Hct was offset by a proportionally greater increase in viscosity, thus leading to a lower Hct-to-viscosity ratio. CONCLUSION: These results indicate the importance of plasma-mediated RBC interactions and suggest that the benefits of transfusion may vary depending on local flow rates (i.e., shear rates) and organ-specific hemodynamics.