An IgG which binds specifically to retro-orbital antigen has been detected in patients with Graves' ophthalmopathy. By means of an assay which detects ophthalmopathic immunoglobulin (OIg) in patients' serum with an antigen prepared from porcine retro-orbital muscle, levels of OIg above the normal reference range were found in 21 of 33 (64%) patients with active untreated ophthalmopathy, in 3 of 12 (25%) with active disease already receiving steroid treatment, and in 3 of 18 (16%) with longstanding inactive eye disease. OIg was found in only 1 of 22 thyroid patients without eye disease. There was no correlation of OIg with thyrotropin-binding-inhibiting immunoglobulin nor with thyroid microsomal antibody, and there was no clear association with thyroglobulin antibody. Ophthalmopathy seems to be distinct from Graves' hyperthyroidism and the autoimmune response is directed to retro-orbital antigens.