The present study has shown that virus can be readily detected by immunofluorescent staining in the central nervous system (CNS) of SJL mice persistently infected with Theiler's murine encephalomyelitis virus (TMEV). Considering the low CNS virus content, large amounts of virus antigen were found in the white matter, the site of demyelinating lesions. Virus antigen was detected in all animals killed after post-infection (PI) Day 21, a time which can be considered as the beginning of the persistent phase of this infection, and the appearance of virus antigen in white matter corresponded closely in time with the onset of demyelination. The pathogensis of this persistent infection can now be reasonably well reconstructed from the temporal observations made in this study. It would appear that between the second and third week PI, virus replication largely shifts from neurons in spinal cord gray matter to other cell types located in white matter. While a lower-grade persistent infection (in terms of the relative number of cells containing virus antigen) is established and maintained in cells in the gray matter and inflammatory and leptomeningeal infiltrates, cells in white matter appear to be mainly responsible for perpetuating the infection. Why these cells should supplant neurons as the most susceptible host cell during the chronic phase of the infection is discussed.