Sixteen cases from the 1980-1981 Taiwan outbreak of hand, foot and mouth disease (HFMD) associated with central nervous system involvement were identified: nine had polio-like syndrome, four had encephalitis or encephalomyelitis, one had cerebellitis, and two had aseptic meningitis. They all had fever, five (31%) had documented myoclonic jerk, and 15 (93%) had HFMD. Their mean blood leukocyte count was 12,490/microL, and five (31%) had leukocytosis (> 15,000/microL); mean cerebrospinal fluid (CSF) leukocyte count was 156/microL, CSF protein was 57 mg/dL and CSF glucose was 57 mg/dL. Two patients with HFMD plus encephalitis died within 1 day of hospitalization, and one of them had acute cardiopulmonary failure mimicking myocarditis. Twenty years later, at least one male patient had sequelae of polio-like syndrome and was therefore exempted from military service. Clinical severity was comparable to the 1998 EV71 epidemic.