The premise that acute non-fatal viral infections of the central nervous system (CNS) predispose to the subsequent development of chronic immune-mediated neurologic disease was investigated. Adult C57Bl/6 mice inoculated peripherally with 10(4) PFU of the A774 strain of Semliki Forest virus (SFV) develop a transient encephalomyelitis and sporadic (less than 20%) mild symptoms of paralysis with demyelination in the cerebellum from which they recover. Such recovered mice were found to develop signs characteristic of experimental allergic encephalomyelitis (EAE) 2 to 8 wk after either immunization with myelin basic protein (MBP) or receipt of 1 to 2 X 10(7) lymph node cells from MBP-primed syngeneic donors. These two methods of disease induction were unsuccessful when applied to normal B6 mice or those previously inoculated with noninfectious SFV. These findings suggest the possibility that virus-induced damage to CNS tissue may facilitate subsequent priming or clonal expansion of pre-existing myelin-reactive lymphoid cells.