Summary. The effect of peroxidative stress on tissue was studied by exposure of red blood cells (RBC) from patients with abetalipoproteinemia to minute amounts of H202 in vitro. Red blood cells from untreated patients showed a marked sensitivity to H202, as evidenced by hemolysis and lipid peroxidation (peroxidative hemolysis).The appearance of lipid peroxidation products in sensitive cells after exposure to H202 was indicated by 1) increases in the 2-thiobarbituric acid (TBA) reaction of trichloroacetic acid extracts, 2) increases in ultraviolet light absorbency of lipid extracts, and 3) decreases in polyunsaturated fatty acids. These changes were accompanied by a decrease in phosphatidyl ethanolamine and phosphatidyl serine in the RBC lipid extract. Similar lipid changes on exposure to H202 were observed in the RBC from vitamin E-deficient rats.Treatment of the patients with d-a-tocopherol polyethylene glycol succinate by mouth, or addition of dl-a-tocopherol to the incubation medium protected the RBC from peroxidative hemolysis. Tocopherol appears to provide a primary biologic defense against peroxidative hemolysis.The presence of nitrite or carbon monoxide, which produced methemoglobin and carboxyhemoglobin, respectively, inhibited peroxidative changes, suggesting a catalytic role for oxy-or deoxyhemoglobin.