Three patients displaying a clinical picture of progressively evolving multifocal action myoclonus and cerebellar ataxia showed a marked intrathecal immune activation, which was persistent over a 2- to 5-year time span in the two serially investigated patients. A thorough search for metabolic, toxic, infectious, or degenerative causes of myoclonus was unsuccessful. The presence of intrathecal immune activation in at least a subgroup of patients with the clinical features of progressive myoclonic ataxia suggests the possibility of immune-mediated damage within the central nervous system in this condition.