The purpose of this study was to determine if differences in antioxidant status between the red blood cells (RBCs) of sickle cell anemia (SCA) patients and controls are responsible for the differential responses to oxidative and osmotic stress-induced hemolysis. Susceptibility to hemolysis was examined by incubating oxygenated and deoxygenated RBCs at 37°C with 73 mM 2,2′ azobis (2-amidinopropane) HC1 (AAPH), a peroxyl radical generator, for up to 3.5 hours. The ability of RBCs to maintain membrane integrity under osmotic stress was determined over a range of diluted saline-phosphate buffer. Sickled RBCs showed a lesser degree of AAPH-induced hemolysis than control groups and were more resistant to osmotic stress-induced hemolysis. SCA patients had higher levels of RBC vitamin E and RBC lipids, but lower RBC GSH, plasma lipids and plasma carotenes than those of the hospital controls. No significant differences were observed in the levels of retinol, vitamin C, vitamin E, MDA and conjugated dienes in plasma, or the levels of MDA and conjugated dienes in RBCs. The results obtained suggest that the differences in antioxidant status between sickled RBCs and controls do not appear to be responsible for their different susceptibility to oxidative or osmotic stress-induced hemolysis observed.