Serum concentrations of T4, T3, and rT3 as well as liver and kidney 5'-deiodinase activity, have been examined in rats stressed by restraint. After immobilization, serum concentrations of T3 decreased significantly (6 hr, -33 +/- 1%; 8 h, -42 +/- 3%), while serum rT3 increased (6 h, +55 +/- 3%; 8 h, +75 +/- 5%). In the same or similarly treated animals, there was a time-dependent reduction in T4 5'-deiodinase activity in both liver (4 h, -23 +/- 2%; 8 h, -43 +/- 3%) and kidney (4 h, -18 +/- 1%; 8 h, -42 +/- 3%) homogenates. The reduction in hepatic and renal T3 production was due to reduced enzyme activity and not to reduced substrate availability. In spite of reductions in serum TSH (4 h, -9 +/- 1%; 8 h, -51 +/- 5%), the serum T4 concentration did not fall. The serum concentration of corticosterone reached 30 times the basal level after 8 h of restraint. Either adrenalectomy or metyrapone treatment, followed by replacement with nonstress doses of B, completely prevented the alterations of iodothyronine metabolism induced by restraint. These results indicate that the stress-induced elevation of plasma glucocorticoids plays a key role in the pathogenesis of the low T3 syndrome in this model. The reduction in serum T3 may be accounted for by a reduction in T3 production by liver and kidney, adding support to the concept that these organs are an important source of plasma T3 in the rat.