Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of reduced tissue responsiveness to thyroid hormone (TH) usually due to mutations in the TH receptor beta gene (TRbeta). We studied pituitary and peripheral tissue responses to graded doses of liothyronine (L-T3) in 5 affected members (2 children and 3 adults) of a family with RTH due to the common TRbeta mutation P453T. Overall, the 5 subjects studied exhibited suppressed thyrotropin response to thyrotropin-releasing hormone of 51% +/- 8%, 12.1% +/- 1.5%, and 6.3% +/- 3% of the 100% baseline on 50, 100, and 200 microg/dL L-T3, respectively. This degree of suppression was greater than that observed in subjects with RTH due to other TRbeta mutations, indicating less resistance. Compared with normal subjects, however, the family described here demonstrated less suppression by L-T3, compatible with their RTH, although of a mild magnitude. The 2 children with RTH demonstrated less L-T3-mediated suppression of prolactin and cholesterol than the adults. Patients often receive thyroid ablative therapy before the diagnosis of RTH and are left with variable degrees of hypothyroidism. Our results demonstrate that graded doses of L-T3 can be used to evaluate RTH patients, even under the condition of limited thyroid reserve, when results are compared with their baseline. We demonstrate that RTH patients can be evaluated either on or off thyroid hormone and still be distinguished from hypothyroid subjects without RTH.