Normal red blood cells (RBCs) are subject to a high level of oxidative stress as a result of the continuous production of the superoxide anion that accompanies hemoglobin (Hb) autoxidation. The superoxide anion is dismutated to hydrogen peroxide (H2O2), which is further converted to the hydroxyl radical through the Fenton reaction in the presence of iron. To cope with oxidative stress, RBCs are equipped with Cu and Zn-dependent SOD (SOD1), catalase, glutathione peroxidase 1 (GPx1), and three isoforms of peroxiredoxin (Prx I, Prx II, and Prx VI). SOD1 converts the superoxide anion to H2O2, which is then removed by catalase, GPx1 and the Prxs. Prx II, the third most abundant protein in RBCs, is responsible for eliminating low concentrations of H2O2, whereas catalase scavenges H2O2 efficiently at high concentrations of the oxidant. Mice that lack Prx II thus develop hemolytic anemia, whereas RBC-related defects are not apparent in catalase-deficient mice. Deficiency of GPx1 renders human RBCs susceptible to oxidant stress. The primary physiologic substrate of GPx1 in RBCs is lipid hydroperoxide. GPx1 is susceptible to irreversible inactivation by its own substrates, likely as a consequence of the irreversible conversion of the active-site selenocysteine residue to dehydroalanine (DHA). Prx enzymes also are inactivated occasionally during catalysis because the active-site cysteine undergoes oxidation to sulfinic acid (Cys–SO2H). Reactivation of Prx I and Prx II is achieved by reduction of the sulfinic moiety catalyzed by sulfiredoxin. No mechanism has been identified for reactivation of the sulfinic form of Prx VI, however. Catalase is resistant to inactivation by its own substrate. In addition to Hb autoxidation, oxidative stress on RBCs can be derived from superoxide anion–generating enzymes (NADPH oxidase, xanthine oxidase) present in the endothelium and leukocytes. Catalase, glutathione peroxidase 1 (GPx1), and Prxs are responsible for the elimination of H2O2 in RBCs. Compared with catalase and GPx, which do not have a specific binding site for H2O2, Prxs function more effectively at low H2O2 concentrations because they do possess a high-affinity binding site for this molecule. Prx II is also much more abundant than the other two enzymes. RBCs express three Prx isoforms: PrxI, PrxII, and PrxVI. During my talk, I will discuss specific roles of PrxII, catalase, and Gpx1 in RBCs, based on the results obtained using RBCs obtained from various KO mice.