The mucosal immune system plays an important role in determining how an individual handles infection by most of the common viruses. Tears form part of this system and participate in mucosal immunity. We examined tears from multiple sclerosis (MS) and control subjects for antibodies to seven common neurotropic viruses. Antibodies to multiple viruses were detected in MS tears, especially when tears were obtained from chronic progressive active patients. In particular, MS patients showed a significantly greater prevalence of tear antibodies to measles, herpes simplex type I, and rubella virus. The tear anti-viral response included IgA as well as IgG antibody and appeared to be independent of serum. Mucosal fluid in MS patients, in addition to cerebrospinal fluid, also shows heightened humoral immune responses to multiple neurotropic viruses.