Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T₃ and high rT₃ levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment. Serum thyroid parameters and the expression of tissue D1-D3 were determined. Serum TSH, T₄, T₃, and the T₃/rT₃ ratio were lower, whereas serum rT₃ was higher than in normal subjects (P < 0.0001). Liver D1 activity was down-regulated and D3 activity was induced in liver and skeletal muscle. Serum T₃/rT₃ ratio correlated positively with liver D1 activity (P < 0.001) and negatively with liver D3 activity (ns). These parameters were independent of the type of insulin treatment. Liver D1 and serum T₃/rT₃ were highest in patients who died from severe brain damage, intermediate in those who died from sepsis or excessive inflammation, and lowest in patients who died from cardiovascular collapse (P < 0.01). Liver D3 showed an opposite relationship. Acute renal failure requiring dialysis and need of inotropes were associated with low liver D1 activity (P < 0.01 and P = 0.06) and high liver D3 (P < 0.01) and skeletal muscle D3 (P < 0.05) activity. Liver D1 activity was negatively correlated with plasma urea (P = 0.002), creatinine (P = 0.06), and bilirubin (P < 0.0001). D1 and D3 mRNA levels corresponded with enzyme activities (both P < 0.001), suggesting regulation of the expression of both deiodinases at the pretranslational level. This is the first study relating tissue deiodinase activities with serum thyroid hormone levels and clinical parameters in a large group of critically ill patients. Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion. These observed changes, in correlation with a low T₃/rT₃ ratio, may represent tissue-specific ways to reduce thyroid hormone bioactivity during cellular hypoxia and contribute to the low T₃ syndrome of severe illness.