Pharmacological doses of glucocorticoids may reduce serum T4 and T3 levels in normal dogs and humans due to hypothalamic-pituitary suppression and/or altered peripheral hormone metabolism. To evaluate the chronic effects of antiinflammatory doses of glucocorticoids on peripheral thyroid hormone metabolism, serum T4 and T3 kinetic studies were performed in five thyroidectomized L-T4-replaced (5 micrograms/kg, sc, daily) normocalcemic male dogs at baseline and after 35 days of oral prednisone (0.55 mg/kg every 12 h). Data were analyzed in a three-pool model, with rapidly (liver and kidney) and slowly (muscle and skin) equilibrating pools exchanging with serum and rapid pool losses. Prednisone lowered the percent free fraction of T4 (to 70% of baseline) and total T3 (to 60%) and free T3 (to 51%) levels without significantly changing total or free T4 or percent free fraction of T3. This was associated with reduced T4 fractional transfer rates from serum rapid (to 39%) and slow (42%) pools and from rapid (to 25%) and slow pools (to 7%) to serum, and increased serum free T4 clearance rates (to 144%) as well as binding in the rapid (162%) and slow (710%) pools. Total T4 clearance and degradation rates were not significantly altered. Significant correlations included T4 binding in the rapid pool with percent free fractions of T4 (r = -0.86), T4 fractional transfer rates from rapid pool to serum with rapid pool T4 binding (r = -0.75), and fractional T4 transfer rates from slow pool to serum with slow pool T4 binding (r = -0.88). In contrast, prednisone increased fractional T3 transfer rates from serum to the slow pool (to 289%) and reduced serum (to 42%) and maximum total body degradation and production rates (to 41%) without altering total or free T3 clearance rates. Fractional T3 transfer rates from the slow pool to serum correlated with slow pool T3 binding (r = -0.84). Prednisone redistributed T4 and T3 from the serum and rapid pools to the slowly equilibrating pool. Thus, the peripheral effects of chronic antiinflammatory doses of prednisone on thyroid hormone metabolism include 1) increased T4 binding to serum carrier proteins, which may contribute to lower T4 transfer rates from serum to extravascular sites and increased extravascular T4 binding; 2) reduced fractional transfer rates of T4 from extravascular sites to serum, which may relate to increased tissue binding of T4; 3) redistribution of T4 and T3 from the serum and rapid pools to the slow pool; and 4) decreased T3 production from T4, resulting in reduced serum total and free T3 levels.