To determine whether antibodies to orbital tissue have a pathogenic role in thyroid-associated ophthalmopathy, the in vitro effects of IgG from patients with thyroid-associated ophthalmopathy on porcine extraocular myoblast growth were studied. Growth of primary extraocular myoblast cultures and extraocular myoblast clones was stimulated by patients' IgG, as measured by [3H]thymidine uptake and bromodeoxyuridine incorporation. Myoblasts responded in a dose-related fashion to increasing concentrations of patients' IgG, and the response was reversed by anti-human IgG. The growth stimulating effect of patients' IgG was relatively specific to extraocular myoblasts, compared to skeletal myoblasts. Individual IgG samples from 36 patients with ophthalmopathy gave rise to higher growth responses of cloned extraocular myoblasts, than either 31 normal controls (p < 0.005), or IgG from 10 patients with Graves' disease without evidence of ophthalmopathy (p < 0.001). Myoblast growth-stimulating antibody did not correlate with thyroid autoantibody levels (thyrotrophin receptor antibody or thyroid microsomal antibody levels), but correlated significantly with binding to extraocular muscle membranes (r = 0.524, p < 0.001). Eye-muscle stimulating antibodies were demonstrable in sera of patients with thyroid-associated ophthalmopathy, and may be responsible for the enlargement of eye muscle in this disease.