Amiodarone and propranolol have been known to inhibit the peripheral conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) but their direct effect on the thyroid gland is not understood. We therefore investigated the action of the two drugs on the functional properties of human thyroid follicles embedded in collagen gel. Amiodarone and propranolol induced a dose-dependent reduction or blocking of the follicular production of cyclic AMP (cAMP), thyroglobulin (Tg) and free triiodothyronine (FT3) under 200 microU/ml medium. Small drug doses and the drug solvents did not affect the follicular secretion. The inhibiting effect of amiodarone and propranolol on follicular production of cAMP, Tg and FT3 appears to result from several factors: (1) inhibition of thyroid 5'-deiodinase; (2) amiodarone high iodine content; (3) a quinidine-like effect of propranolol involving a membrane-stabilizing mechanism.