In order to evaluate the effects of amiodarone on thyroid function in chronically treated patients, 43 consecutive patients, who had been taking a mean weekly dose of 1420 +/- 488 mg for more than 9 months (mean 16.5 months), were studied. In a first evaluation, three patients with hypothyroidism and two with hyperthyroidism were discovered. In the remaining 38 patients, mean T4 (131 +/- 38 nmol/L) and rT3 (0.85 +/- 0.3 nmol/L) levels were significantly higher than reference values (p less than 0.05 and p less than 0.001, respectively), and mean T3 levels (1.89 +/- 0.73 nmol/L) were significantly lower (p less than 0.001). Thirteen patients showed hyperresponsiveness to thyrotropin-releasing hormone (TRH) stimulation testing. In a second evaluation, performed 12 to 18 months later, two new cases of hypothyroidism were discovered. T3 levels showed significantly lower values (p less than 0.02) than in the first evaluation, whereas basal thyroid-stimulating hormone levels and levels 30 and 60 minutes after TRH stimulation were significantly higher than those in the first evaluation (p less than 0.001). Five new hyperresponders to TRH were found. In the present series, the progressive appearance of clinical thyroid dysfunction with an elevated total incidence (16%) is demonstrated. Moreover, a progressively high prevalence of hyperresponsiveness to TRH stimulation is shown. These findings indicate that chronic amiodarone administration may carry a high risk of thyroid dysfunction.