Differences in the epitopes of thyroid-stimulating antibodies (TSAbs) from patients with untreated Graves' disease were compared with long-term response to antithyroid drugs. Epitopes were measured using Chinese hamster ovary cells transfected with wild-type human TSH receptor (TSHR) and two receptor chimeras, wherein TSHR residues 9-165 or 90-165 had been substituted with comparable residues of the LH/chorionic gonadotropin receptor. Of 159 patients studied, 52 (32.7%) exhibited positive TSAb activity with one or both chimera lines (heterogeneous group), and 107 (67.3%) had no activity with either (homogeneous group). Independent of all other parameters, patients with heterogeneous epitopes responded more favorably to oral antithyroid drugs than patients with homogeneous epitopes (65.4% vs. 41.9%, P = 0.011: estimated odds ratio by logistic regression, 2.17). Although most clinical parameters were not different at presentation, significant differences in the size of goiters, total T(3) concentrations, and titers of TSH-binding inhibitory Igs were evident in the successfully treated group (n = 80) by comparison to the group of patients whose treatment failed (n = 79). Alone, these three parameters did not predict outcome; however, when either of these parameters were considered together with epitope heterogeneity, predictability of a positive therapeutic response was increased to nearly 80%. Thus, the presence of TSAbs with a heterogeneous epitope in a patient with Graves' disease is not only associated with a favorable response to antithyroid drug treatment, it may help predict the response to treatment when the patient is initially seen.