To explore the hypothesis that alteration of T3 receptor expression may be an important mechanism controlling the tissue effects of thyroid hormones in the "sick euthyroid" syndrome, specific triiodothyronine (T3) receptor mRNAs were measured in tissues from normal subjects and from patients with liver disease, chronic renal failure, or with multiple organ failure on an intensive care unit (ICU). In all patient groups circulating free thyroxine and free T3 were reduced, while thyroid stimulating hormone remained normal. In patients with liver or renal disease, there were significant increases in levels of both alpha and beta T3 receptor mRNAs in peripheral mononuclear cells (PMNCs); in ICU patients there was a significant increase in beta mRNA. In patients with liver disease increases in T3 receptor mRNAs were not confined to PMNCs but were also found in liver biopsy specimens when levels were compared with those in normal donor liver. After liver transplantation, receptor mRNAs in PMNCs were similar to those in controls; likewise beta mRNA was similar in liver tissue to normal liver. There was, however, persistent elevation in alpha receptor mRNA. Increases in T3 receptor expression in non-thyroidal illness may be responsible for the maintenance of euthyroidism in the face of reduced levels of circulating thyroid hormones.