Low levels of antinuclear antibodies (ANAs) were found by indirect immunofluorescence in the serum of patients with multiple sclerosis (MS). Antibodies were found in 22 (81%) of 27 patients with MS and four (20%) of 20 healthy control subjects, with human epithelial (HEp-2) cells as substrate. Antinuclear antibody titers ranged from 8 to 32 in patients with MS and rarely reached above 8 in control subjects. The most common fluorescence patterns produced by MS serums were diffuse, fine speckled, and diffuse with fine-speckled nuclear fluorescence. Large nucleolar speckles and cytoplasmic fine speckles were also seen. Similar, although stronger patterns were seen in control subjects with positive tests for systemic lupus erythematosus. No correlation was found between ANA and antimeasles antibody titers. The presence of a heterogeneous population of circulating antibodies to a variety of nuclear and cytoplasmic antigens lends further support to the concept that altered immune reactivity exists in MS.