Guamanian amyotrophic lateral sclerosis with parkinsonism-dementia (ALS/PD) has been the subject of intensive study since its discovery in 1947 because of its extraordinarily high incidence in a small ethnic group (Chamorros) whose dietary lack and customs have suggested possible causes. As yet, these and other suspected causes have eluded proof. Because of marked similarities between Guamanian ALS/PD and late onset post-encephalitic (encephalitis lethargica) parkinsonism and ALS it is suggested that they have a common cause. The parkinsonism and ALS in the two disorders are clinically very similar and neuropathological studies have shown a very similar distribution of neurofibrillary tangles in neurons. Some clinical differences, such as ocular features in the post-encephalitic cases and dementia in Guamanian ALS/PD, can be explained by differences in the severity of infection and the interval between the encephalitis and onset of sequelae. Although unproven, influenza A (HswilNl strain) has long been suspected as the cause of encephalitis lethargica because of simultaneous pandemics of the two diseases in the 1920s. Because influenza A can persistently infect cells and has a marked propensity to mutate it is an optimal candidate among other RNA viruses for delayed nervous system infection as a possible cause of ALS/PD.