A virologic comparison was made of 144 patients with multiple sclerosis, 34 of their healthy siblings, and 40 patients with other neurologic diseases (OND). Antibodies in serum and cerebrospinal fluid (CSF) to vaccinia and measles viruses were measured, and these were correlated in the multiple sclerosis patients with the clinical characteristics of their disease. The CSF antibody to vaccinia virus was more frequent and at a higher titer in multiple sclerosis patients than in either control group. Moreover, a statistically significant increase was found in both frequency and titer of CSF vaccinia antibody in patients with the progressive form of the disease as compared with those classified as relapsing-remitting. Statistically significant differences between multiple sclerosis patients and their siblings were not observed for CSF or serum measles virus antibody, although both groups had significantly higher serum antibody titers than patients with OND.