Basal levels of thyroid-stimulating hormone (TSH) as determined by a highly sensitive immunoradiometric assay (IRMA) were evaluated in 30 clinically euthyroid patients receiving levothyroxine (T4) replacement therapy for primary hypothyroidism. In each patient, the serum TSH level had been normal as determined by conventional TSH radioimmunoassay while the patient had been receiving a constant dosage of T4 for at least three months before the study. Correlation of the TSH levels by IRMA with the concurrent concentrations of serum T4 and triiodothyronine (T3) showed that basal TSH levels by IRMA were not predictable from the serum T4 and/or T3 levels. We observed a relatively high frequency of suppression of basal TSH levels (8/30, 27%), a finding compatible with, though not necessarily indicative of, overmedication with T4. In view of the reasonable suspicion that modest but protracted overmedication with T4 may be detrimental and that suppressed TSH levels are commonly observed in conventionally managed patients, and since suppression of TSH levels is now identifiable, it seems prudent to revise the guidelines of T4 replacement therapy accordingly. In addition to maintaining clinical euthyroidism, we propose that titrating the T4 dosage to establish lower normal TSH concentrations without suppression (eg, 0.1 to 3.0 microU/ml) would assure the resolution of frank hypothyroidism, reduce the likelihood of persistent goiter, and minimize the potential for subtle but chronic overmedication.