Dietary exposure to phytosterols has increased in recent years due to the incorporation of these compounds into cholesterol-lowering products. Previous studies have investigated the cytotoxic effects of the oxidized derivatives of beta-sitosterol and determined that phytosterol oxidation products (POP) have a similar but less potent toxicity compared to their cholesterol equivalents. In the present study, the cytotoxicity of the oxidized derivatives of stigmasterol were investigated in the U937 cell line. The stigmasta-5,22-diene-3 beta,7 beta-diol (7 beta-OH), 5,6-epoxystigmasta-22,23-diol (epoxydiol), 5,6,22,23-diepoxystigmastane (diepoxide), and (22R,23R)-stigmast-5-ene-3 beta,22,23-triol (22R,23R-triol) derivatives were identified as the most cytotoxic, and the mode of cell death was identified as apoptosis in cells incubated with 7 beta-OH, epoxydiol, and diepoxide stigmasterol. The antioxidants alpha-tocopherol, gamma-tocopherol, and beta-carotene did not protect against apoptosis induced by 7 beta-OH and diepoxide stigmasterol; however, a-tocopherol was found to protect against epoxydiol-induced apoptosis. The cellular antioxidant, glutathione, was depleted and the apoptotic protein. Bcl-2, was down-regulated by the stigmasterol oxides identified as apoptotic.