Female Chinese hamsters (n = 10) were immunized with Chinese hamster ovary (CHO) cells that expressed the human TSH receptor (TSHR) to generate a model of Graves' disease. TSHR-autoantibodies (TSHR-Ab) were determined by CHO-TSHR. Two hamsters with stimulating TSHR-Ab showed thyrocyte hypertrophy associated with a focal lymphocytic infiltration. CHO-TSHR were then stimulated with interferon gamma to enhance major histocompatibility complex class II expression. However, after immunization no stimulating TSHR-Ab were detected, but blocking TSHR-Ab were found in three of five animals. The thyroid glands from these hamsters showed marked thinning of thyroid epithelial cells, indicative of early thyroid atrophy consistent with a TSHR blocking antibody, but no lymphocytic infiltration. Lastly, female Armenian hamsters were immunized with an adenovirus construct incorporating wild-type TSHR. High titers of TSHR-Ab were induced effectively, but the thyroid hypertrophy observed was not associated with a lymphocyte infiltration. In summary, we demonstrated that the hamster could serve as a model of TSHR autoimmunity and that an adenoviral vector produced higher levels of TSHR-Ab than more conventional immunization with cells. The data also indicated that the intrathyroidal cellular immunity in this model was not related to TSHR-Ab formation and was an independent reflection of the T-cell immune response to TSHR antigen.