The human red blood cell (RBC) is known to be susceptible to oxidant damage, with both structural and functional properties altered consequent to oxidant attack. Such oxidant-related alterations may lead to changes of RBC rheologic behavior (i.e., deformability, aggregability). Two different models of oxidant stress were used in this study to generate superoxide anions either internal or external to the RBC. Our results indicate that generation of superoxide within the RBC by phenazine methosulfate decreases RBC deformability without effects on cell aggregation. Conversely, superoxide generated externally by the xanthine oxidase-hypoxanthine system primarily affects RBC aggregability: the shear rate necessary to disaggregate RBC was markedly increased while the extent of aggregation decreased slightly. Increased disaggregation shear rate (i.e., greater aggregate strength) as a result of superoxide radical damage may adversely affect the dynamics of blood flow in low-shear portions of the circulation, and may also play a role in the no-reflow phenomena encountered after ischemia-reperfusion.