Argyrophilic grain disease is a progressive degenerative disorder of the human brain which becomes increasingly prevalent with advancing age. The disease entails multiple neuronal systems and results from cytoskeletal degeneration in only a few neuronal types and in oligodendrocytes. Immunoreactions for abnormally phosphorylated tau protein permit identification of the changes. Only a fraction of the emerging abnormal fibrillary material shows a pronounced argyrophilia. Essential for neuropathological diagnosis is assessment of the presence of small spindle-shaped argyrophilic grains in neuronal processes. The anteromedial portion of the temporal lobe bears the brunt of the lesions. Grains generally can be found in abundance in the entorhinal region, the first Ammon's horn sector, the subcortical nuclear complex of the amygdala, and the hypothalamic lateral tuberal nucleus. Frequently, the lesions co-exist with those typically found in Alzheimer's disease or other tauopathies. Owing to the characteristic grains, the disorder easily can be differentiated from other tauopathies. 2661 non-selected brains obtained at autopsy included 125 cases of argyrophilic grain disease (5%) from individuals between 51 and 96 years of age (mean 79 years) . The fact that the same material contained 146 cases of fully developed Alzheimer's disease (6%) supports the view that argyrophilic grain disease is not a rare disorder. Its prevalence with and without concomitant neurofibrillary changes of the Alzheimer type grows with increasing age. Argyrophilic grain disease merits attention because of its frequent occurrence and its potential to cause severe brain dysfunction.