Treatment with the antiarrhythmic agent amiodarone results in alterations in thyroid hormone metabolism, and can induce either hypothyroidism or hyperthyroidism (amiodarone-associated thyrotoxicosis, AAT). AAT occurs in patients both with and without preexisting goiter. In our study of the nongoitrous variety, the effect in vitro of amiodarone treatment and of concurrent treatment with potential inhibitors on thyroid cells (FRTL-5) was assessed by measuring the release of radiolabeled chromium (51Cr). In addition, thyroid histopathology was evaluated in autopsy specimens from six amiodarone-treated patients who had no pretreatment evidence of thyroid disease. Histopathologic examination revealed minimal or no evidence of thyroid follicular damage in specimens from amiodarone-treated euthyroid patients (n = 4). In contrast, moderate to severe follicular damage and disruption were present in glands from patients with AAT (n = 2). Studies in vitro showed amiodarone to be cytotoxic to thyroid cells; this effect was inhibited by treatment with dexamethasone (10(-3) mmol) or perchlorate (2.5 micrograms/mL). In summary, we demonstrate evidence in vitro and in vivo of amiodarone-induced thyroid follicular damage and disruption in specimens from patients with nongoitrous AAT and in cultured normal thyroid cells. In addition, we demonstrate inhibition of this effect following treatment in vitro with dexamethasone or perchlorate. Our findings support the concept that nongoitrous (type I) AAT results from direct drug toxicity with disruption of thyroid follicles and subsequent release of preformed thyroid hormone.