Recent studies have implicated increased oxidative stress in the pathogenesis of Alzheimer's disease (AD). Increased lipid peroxidation and decreased polyunsaturated fatty acid levels have been described in the brain in AD. Four-hydroxynonenal (HNE), an aldehyde product of lipid peroxidation, has been demonstrated to be a neurotoxin in tissue culture and in vivo studies and is elevated in ventricular fluid in AD. We report here an increase in mean free HNE in multiple brain regions in AD compared with age-matched control subjects. These increases reached statistical significance in the amygdala and hippocampus and parahippocampal gyrus, regions showing the most pronounced histopathological alterations in AD. This study, in conjunction with cell culture studies, suggests that HNE may be an important substance in the pathogenesis of neuron degeneration in AD.