Rats of the Fischer 344 (F344) strain are resistant to experimental allergic encephalomyelitis (EAE) induced by active immunization with guinea pig myelin basic protein (MBP) in complete Freund's adjuvant whereas Lewis (LEW) rats are susceptible even though both strains share the same I-A-like class II alleles of the MHC RT1.B locus. To determine factors that might contribute to this difference in disease susceptibility, we have compared in these two strains (1) the frequency of MBP-reactive T cells in the lymph nodes and spleens of MBP-immunized animals, (2) the dominant MBP epitopes recognized by responding T cells, (3) the ability of MBP-reactive T cells to enter the central nervous system (CNS), and (4) the frequency of CD8+ regulatory T cells (RTC) whose activity is functionally antagonistic to MBP-reactive T cells. The results indicate that MBP-reactive T cell numbers are similar in MBP-immunized F344 and LEW rats, they both recognize p68-88 as the dominant encephalitogenic epitope of MBP, and MBP-reactive T cells isolated from immunized rats and adoptively transferred to naive animals are similarly effective in penetrating the blood-brain barrier and entering the CNS, leading to pathogenesis in EAE. However, the frequency of RTC that functionally inhibit MBP-reactive T cells is greater in F344 rats.