Free radicals and oxidative stress-induced neuronal cell death have been implicated in a variety of neurological disorders. Therefore, neuroprotection is of primary interest in basic and preclinical neuroscience. Here it is shown that RU486 (mifepristone), a potent antagonist of progesterone and glucocorticoid receptors, protects rat primary hippocampal neurons, clonal mouse hippocampal cells and organotypic hippocampal slice cultures against oxidative stress-induced neuronal cell death. 10-5 M RU486 prevents intracellular peroxide accumulation and cell death induced by amyloid β protein, hydrogen peroxide and glutamate, neurotoxins that have been implicated in certain neurodegenerative disorders, including Alzheimer's disease. RU486 has a significant protective effect that is independent of the presence and activation of glucocorticoid or progesterone receptors. The neuroprotective activity of this well-studied drug may have an impact on therapeutic interventions for neurodegenerative conditions which involve peroxidation processes. such as stroke and Alzheimer's disease.