This study investigates the antioxidant defenses and lipid peroxidation in human blood plasma under two types of oxidizing conditions: exposure to aqueous peroxyl radicals and stimulation of polymorphonuclear leukocytes (PMNs). The results show that endogenous antioxidants such as ascorbate, sulfhydryl groups, bilirubin, urate, and α-tocopherol are consumed in a specific order, with ascorbate being the first to be depleted. Once ascorbate is completely oxidized, micromolar concentrations of lipid hydroperoxides of plasma phospholipids, triglycerides, and cholesterol esters appear, even though other antioxidants remain at high concentrations. Nonesterified fatty acids are protected from peroxidative damage due to site-specific antioxidant protection by albumin-bound bilirubin and possibly by albumin itself. In contrast, lipid hydroperoxides of phosphatidylcholine, linoleic acid, and cholesterol are degraded in plasma, indicating the presence of a selective peroxidase activity. The study also shows that activated PMNs lead to rapid oxidation of ascorbate and the formation of lipid hydroperoxides, while other antioxidants like bilirubin and α-tocopherol remain largely unaffected. The findings suggest that ascorbate is the most effective antioxidant in protecting lipids from peroxidative damage by aqueous oxidants, and that its depletion is a critical factor in the formation of lipid hydroperoxides. The study highlights the importance of ascorbate in preventing oxidative stress-related diseases such as cancer, atherosclerosis, and aging, and suggests that ascorbate supplementation could be beneficial in preventing lipid hydroperoxide formation. The results also indicate that the effectiveness of antioxidants in preventing lipid peroxidation varies, with ascorbate being the most effective, followed by bilirubin and α-tocopherol. The study provides insights into the mechanisms of lipid peroxidation and antioxidant defense in human plasma, and has implications for the prevention and treatment of oxidative stress-related diseases.This study investigates the antioxidant defenses and lipid peroxidation in human blood plasma under two types of oxidizing conditions: exposure to aqueous peroxyl radicals and stimulation of polymorphonuclear leukocytes (PMNs). The results show that endogenous antioxidants such as ascorbate, sulfhydryl groups, bilirubin, urate, and α-tocopherol are consumed in a specific order, with ascorbate being the first to be depleted. Once ascorbate is completely oxidized, micromolar concentrations of lipid hydroperoxides of plasma phospholipids, triglycerides, and cholesterol esters appear, even though other antioxidants remain at high concentrations. Nonesterified fatty acids are protected from peroxidative damage due to site-specific antioxidant protection by albumin-bound bilirubin and possibly by albumin itself. In contrast, lipid hydroperoxides of phosphatidylcholine, linoleic acid, and cholesterol are degraded in plasma, indicating the presence of a selective peroxidase activity. The study also shows that activated PMNs lead to rapid oxidation of ascorbate and the formation of lipid hydroperoxides, while other antioxidants like bilirubin and α-tocopherol remain largely unaffected. The findings suggest that ascorbate is the most effective antioxidant in protecting lipids from peroxidative damage by aqueous oxidants, and that its depletion is a critical factor in the formation of lipid hydroperoxides. The study highlights the importance of ascorbate in preventing oxidative stress-related diseases such as cancer, atherosclerosis, and aging, and suggests that ascorbate supplementation could be beneficial in preventing lipid hydroperoxide formation. The results also indicate that the effectiveness of antioxidants in preventing lipid peroxidation varies, with ascorbate being the most effective, followed by bilirubin and α-tocopherol. The study provides insights into the mechanisms of lipid peroxidation and antioxidant defense in human plasma, and has implications for the prevention and treatment of oxidative stress-related diseases.