The durability of immunoprotection against experimental autoimmune encephalomyelitis (EAE) was assessed in guinea-pigs, using a standard protective inoculum (10 μg) of basic protein of myelin (BPM) in Freund's incomplete adjuvant. Protected animals withstood incrementally greater challenges with BPM in Freund's complete adjuvant, up to the massive dose of 10 mg. Protection was not readily overridden by challenge with either whole human brain or guinea-pig spinal cord, indicating that BPM is the major if not only encephalitogen in neural tissue. Protected animals, after encephalitogenic challenge, either developed no disease or a mild attenuated form of EAE; a few developed either chronic or relapsing types of EAE. Immunoprotection correlated with reduced cell-mediated immunity to BPM as judged by cutaneous reactions, but not with humoral antibodies to BPM as detected by radioimmunoassay (total antibody) or passive cutaneous anaphylaxis (IgG1 class); total and IgG1 antibody increased with repetitive encephalitogenic challenge. Whilst immunoprotection is related to functional changes in T cells, it remains uncertain whether there is potentiation of a class of suppressor T cells, or inhibition of a class of cytotoxic T cells, or both.