We tested the proliferative responses of peripheral blood mononuclear cells from 61 patients with multiple sclerosis, 56 healthy control subjects and 52 patients with other neurological diseases to seven synthetic peptides of myelin proteolipid protein (PLP) and 19 synthetic peptides of myelin basic protein (MBP). Increased proliferative responses to two overlapping PLP peptides, PLP184-199 and PLP190-209 were found significantly more frequently in blood from patients with relapsing-remitting or secondary progressive multiple sclerosis (52.3%), but not from those with primary progressive multiple sclerosis (18.2%), than in that from healthy control subjects (8.9%) and patients with other neurological diseases (20.8%). Reactivity to these PLP peptides was most frequently seen in blood from patients with multiple sclerosis of 6-15 years duration and with moderate to severe disability (Kurtzke's Expanded Disability Status Scale > 4.0); the blood from 15 of 19 patients in this group reacted to one or both of the peptides. Both peptides could be recognized by short-term T-cell lines specific for whole PLP, and lines specific for one or other of the two overlapping peptides were able to recognize whole PLP, indicating that these peptides can be processed naturally from the intact molecule. This region of PLP is encephalitogenic in a number of strains of mice. Samples from multiple sclerosis patients did not react more frequently to any of the MBP peptides than those from healthy control subjects. The proportions of patients with other neurological diseases whose blood responded to the MBP peptides that most frequently elicited responses in blood from multiple sclerosis patients were significantly lower than the proportions of multiple sclerosis patients and healthy control subjects whose blood responded to these peptides.