A chemiluminescent TSH assay (detection limit, less than 0.01 mU/L) allows for accurate measurement of subnormal TSH concentrations. We retrospectively analyzed serum TSH and the free T4 (fT4) index of 460 consecutive endocrine clinic visits to determine the usefulness of TSH measurements alone in the assessment of thyroid function. Additionally, case histories were presented nonconsecutively to one of us (TSH alone or TSH with fT4) to determine if knowledge of the fT4 level would alter management. Of hypothyroid patients on replacement therapy (n = 127), 60% had concordant fT4 and TSH, 14% had subnormal TSH with normal fT4, 18% had high TSH with normal fT4, and 4% normal TSH with high fT4; only 4% were managed differently when the fT4 level was known in addition to TSH. Of the patients receiving suppressive therapy with TSH levels above 0.05 mU/L (n = 81), only 4% were managed differently when fT4 was known; 4% had high fT4. With TSH levels below 0.05 mU/L (n = 64), knowledge of fT4 was felt to be necessary for management in all cases; 53% had high fT4. Twenty-three of 46 (50%) patients being treated for hyperthyroidism had discordant TSH and fT4, including 7 patients with low TSH and low fT4. Two of 21 (10%) patients screened with pituitary/hypothalamic disease had discordant TSH and fT4, and 4 of 9 (44%) patients treated with L-T4 for secondary hypothyroidism had subnormal TSH. Knowledge of fT4 was felt to be necessary in all these cases. We conclude that TSH alone is sufficient for screening and monitoring L-T4 replacement or suppression therapy if TSH levels are above 0.05 mU/L. These patients account for the majority of visits to our endocrine clinic. TSH alone is misleading in pituitary disease and during the treatment of hyperthyroidism. fT4 is needed if TSH levels are less than 0.05 mU/L to assess the degree of hyperthyroidism.