The effects of amiodarone on heart weight, production of 14C-CO2 from labelled glucose, myosin ATPase activity, and myosin isoenzyme patterns were determined by comparing control and amiodar-one-treated male Wistar rats. Since it has been suggested that amiodarone may interfere with thyroid hormone action on the heart, similar experiments were also carried out in hypothyroid and amiodar-one-plus-triiodothyronine(T3)-treated rats, and the data were compared to those obtained in amio-darone-treated rats. Amiodarone treatment for 6 weeks resulted in lower heart weight, decreased atrial production of 14C-CO2 from labelled glucose, decreased myosin Ca-ATPase activity, and preferential synthesis of V3 isomyosin. These effects were similar to those observed in hypothyroid rats but were lesser in magnitude. T3 treatment of amiodarone-treated rats reversed all the changes induced by amiodarone. Serum thyroxine (T4) was higher in amiodarone-treated than in control rats, while serum T3 was similar. Serum T3 was higher in the amiodarone-plus-T3 than in the amiodarone-treated group. These results show that 1) amiodarone-induced changes resemble hypothyroid ism with respect to cardiac myosin expression and atrial CO2 production, 2) amiodarone causes hypothyroid-like changes despite normal serum T3 and increased serum T4, and 3) T3 reverses the effects of amiodarone. These data support the hypothesis that amiodarone inhibits the action of thyroid hormone on the heart.