Down's syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation. Development of the DS brain is associated with decreased neuronal number and abnormal neuronal differentiation, and adults with DS develop Alzheimer's disease. The cause of the neurodegenerative process in DS is unknown. Here we report that cortical neurons from fetal DS and age-matched normal brain differentiate normally in culture, but DS neurons subsequently degenerate and undergo apoptosis whereas normal neurons remain viable. Degeneration of DS neurons is prevented by treatment with free-radical scavengers or catalase. Furthermore, DS neurons exhibit a three- to fourfold increase in intracellular reactive oxygen species and elevated levels of lipid peroxidation that precede neuronal death. These results suggest that DS neurons have a defect in the metabolism of reactive oxygen species that causes neuronal apoptosis. This defect may contribute to mental retardation early in life and predispose to Alzheimer's disease in adults.