To delineate the metabolic fate of thyroid hormone in prolonged critically ill rabbits, we investigated the impact of two dose regimes of thyroid hormone on plasma 3,3'-diiodothyronine (T-2) and T4S, deiodinase type 1 (D1) and D3 activity, and tissue iodothyronine levels in liver and kidney, as compared with saline and TRH. D2-expressing tissues were ignored. The regimens comprised either substitution dose or a 3- to 5-fold higher dose of T-4 and T-3, either alone or combined, targeted to achieve plasma thyroid hormone levels obtained by TRH. Compared with healthy animals, saline-treated ill rabbits revealed lower plasma T-3 (P = 0.006), hepatic T-3 (P = 0.02), and hepatic D1 activity (P = 0.01). Substitution-dosed thyroid hormone therapy did not affect these changes except a further decline in plasma (P = 0.0006) and tissue T-4 (P = 0.04). High-dosed thyroid hormone therapy elevated plasma and tissue iodothyronine levels and hepatic D1 activity, as did TRH. Changes in iodothyronine tissue levels mimicked changes in plasma. Tissue T-3 and tissue T-3/reverse T3 ratio correlated with deiodinase activities. Neither substitution- nor high-dose treatment altered plasma T-2. Plasma T4S was increased only by T-4 in high dose. We conclude that in prolonged critically ill rabbits, low plasma T-3 levels were associated with low liver and kidney T-3 levels. Restoration of plasma and liver and kidney tissue iodothyronine levels was not achieved by thyroid hormone in substitution dose but instead required severalfold this dose. This indicates thyroid hormone hypermetabolism, which in this model of critical illness is not entirely explained by deiodination or by sulfoconjugation.