A high frequency of amyotrophic lateral sclerosis in the mountainous Kii peninsula of Japan was confirmed by epidemiologic surveys in 1961 and 1962, yielding four positive and seven suspected cases in a population of 1,219. Mortality statistics for the 20-year period from 1946 through 1965 revealed a total of 21 deaths, a rate of 14.3 per 1,000, which is 23.8 times higher than the average of the whole of Japan with a mortality rate of 0.4 per 1,000. Genetic studies suggest an irregular, autosomal, dominant mode of inheritance. Neuropathologically, widespread abnormalities extended from the spinal cord to medulla, pons, midbrain, basal ganglia, and cerebral cortex. Granulovacuolar degeneration and Alzheimer's neurofibrillary change, rarely seen in amyotrophic lateral sclerosis in other parts of Japan, and thought to be unique in Guam, were demonstrated in four cases in Kii. Chemical analysis by the neutron-activation method indicated a different distribution of manganese content in brain tissue from a person with amyotrophic lateral sclerosis and from a normal person.