Rabbits immunized over a long period of time with serial injections of aqueous preparations of either bovine thyroglobulin or chemically altered rabbit thyroglobulin develop progressive thyroiditis. As is short-term thyroiditis in rabbits and mice, this thyroiditis is characterized by lesions and cellular infiltration similar to that observed in Arthus reactions. Once the progressive thyroiditis is established, the rabbits respond readily to subsequent injections of native rabbit thyroglobulin. No significant reduction of lesions or circulating antibody is observed when injections of native rabbit thyroglobulin are substituted for the preparations used to induce the disease. Cell-mediated hypersensitivity to rabbit thyroglobulin, as evidenced by MIF activity, develops in rabbits after prolonged immunization with altered or cross-reacting thyroglobulin. It is suggested that this activity develops as a result of a loss in the unresponsive state in T lymphocytes. The data indicate that it is the persistence of circulating antibody to autologous thyroglobulin which sequesters autologous thyroglobulin from peripheral lymphoid tissue, and thus, results in the loss of the unresponsive state in lymphocytes of these tissues. It is suggested that similar events may be involved in the development of cell-mediated hypersensitivity in thyroiditis in humans.