The overall efficiency of standard levothyroxine replacement therapy for hypothyroidism was observed in 2488 patients. The treatment outcome was acceptable in 90% of patients with spontaneous hypothyroidism and in 82% of patients with induced hypothyroidism following either surgery or I131 treatment. The pituitary-thyroid feedback control was investigated in properly treated randomly selected 250 hypothyroid and 110 athyreotic patients and was compared with 210 healthy subjects. Unlike normal TSH distribution in controls, most hypothyroid patients displayed high normal, and the majority of athyreotic patients, low normal TSH values. In hypothyroid patients the TSH median was significantly higher than in controls, with a significantly higher T4 level, suggesting a decreased ability of T4 to suppress TSH, which was also supported by a lower T4/TSH ratio (TSH Suppressibility Index). Impaired TSH suppressibility in athyreotic patients could be overcome by administering a significantly higher levothyroxine dose (by 50%) than in hypothyroid patients. This treatment resulted in a significantly higher T4 and a significantly lower TSH than in hypothyroid patients and controls. These results, together with an excessively high T4/TSH ratio, raise doubts about athyreotic patients being overtreated. A positive correlation of the T4 vs T4/TSH ratio and a negative correlation of the TSH vs T4/TSH ratio were found in all groups but in different T4 and TSH concentration levels: lower for controls and higher for hypothyroid/athyreotic patients. For the same T4/TSH ratio (TSH Suppressibility Index) a lower serum T4, together with a lower TSH was found in euthyroid subjects than in hypothyroid and athyreotic patients. The difference in TSH suppressibility suggested an impaired pituitary-thyroid feedback control in hypothyroidism and athyreosis. Serum T3 levels for both groups of hypothyroid patients were significantly lower in comparison to healthy subjects, in spite of simultaneously observed higher T4 concentrations. An increased T4/T3 ratio indicated a decreased peripheral T4 to T3 conversion. A decreased serum T3 emerged as a major cause of a diminished T4 ability to adequately suppress (normalize) TSH. The beneficient role of LT3 in combined replacement therapy for hypothyroidism was observed in a defined group of athyreotic patients who failed to suppress (normalize) TSH even with a very high levothyroxine dose and supranormal T4 values. A combined therapy with liotriiodothyronine significantly decreased the need for levothyroxine and normalized both serum TSH and T4.