The cellular immune response to measles virus, as measured by lymphocyte proliferation in normal individuals, is considerably lower than that to mumps or vaccinia viruses, and stable multiple sclerosis patients do not differ significantly from the norm. The response to these viruses was studied in 28 twin sets both concordant and discordant for multiple sclerosis. Normal responses to mumps and vaccinia viruses occurred throughout. Seven affected twins manifested a persistently elevated response to measles virus, whereas the unaffected twins had a (normal) low response. The differences were unrelated to differences in T cell subsets, unusual kinetics of the response, or differential susceptibility of lymphocytes to the effects of measles virus infection in vitro. The specificity of the response resides in an E+ subpopulation, and the addition of low-responder E+ cells to high-responder E+ cells failed to identify an active low-responder suppressor population. These findings suggest the presence of clonally expanded measles-specific T cell populations in the high responders with multiple sclerosis.