The authors examined the ability of antioxidants to prevent in vitro oxidant damage to the sickle red blood cell (RBC). One millimolar ascorbic acid and α-mercaptopropionyl-glycine significantly (p < 0.005) protected against RBC Heinz body formation during incubation with acetylphenylhydrazine, while cysteine, cysteamine, and methionine did not. The effect of ascorbic acid was concentration dependent with concentrations as low as 0.1 mM having significant antioxidant effects. Ascorbic acid protected the RBC against hydrogen peroxide induced hemolysis as well (p < 0.05). Ascorbic acid had a significant stimulatory effect on the rate of glucose oxidation by the pentose phosphate shunt (PPS), especially in the sickle RBC. Ascorbic acid did not protect the RBC from a patient with chronic hemolytic anemia due to G6PDTorrancefrom Heinz body formation, suggesting that an intact PPS is necessary for ascorbic acid to express its antioxidant properties. These data suggest that clinical trials should be undertaken to examine the efficacy of ascorbic acid in the treatment of SCD.