We have investigated the effect of thyroid hormone on the mitochondrial membrane permeability properties in a hypothyroid rat model. The role played by calcium in affecting these properties has been also examined. Cyclosporin A-sensitive mitochondrial calcium efflux, swelling, and external release of matrix proteins are events that occur normally during the permeability transition process induced by calcium loading of mitochondria. We demonstrate that these events are impaired in mitochondria isolated from the liver of hypothyroid rats, even in the presence of high calcium content. However, after thyroid hormone administration to hypothyroid rats, the mitochondrial permeability transition process in response to calcium loading is restored. Consequently, mitochondrial calcium efflux, swelling and release of matrix proteins, like glutamate dehydrogenase, malate dehydrogenase and aspartate aminotransferase occur. These effects are abrogated by the concomitant administration of Cyclosporin A. The results of the present study suggest that hypothyroidism may be a potential source of adverse effects in patients receiving Cyclosporin A.