Increasing evidence suggests a relevant role for thyroid gland in maintaining hypophysis-thyroid homeostasis even in patients treated with oral thyroxine. Aim of the study was to compare the daily dose of thyroxine required to attain subnormal serum TSH levels in patients with nontoxic goitre before and following total thyroidectomy. To address this question we have studied: a) 15 patients (8 women and 7 men; median age=53 years) with nontoxic goitre (NTG) and no evidence of autonomous functioning nodule, prospectively analyzed before and after total thyroidectomy for differentiated thyroid carcinoma and b) a cohort of 45 randomly selected patients (35 women and 10 men; median age=51 years) with similar characteristics submitted to total thyroidectomy. Thirty-nine randomly selected T4-treated patients with NTG (33F, 6M; median age=46 years) represented the reference group. In all these patients we compared the dose of thyroxine (normalized by Kg body weight/day) required to stably attain plasma TSH levels to within 0.10.2 mU/l. No patients were taking drugs or had evidence of other diseases, known to interfere with the absorption of thyroxine. In the patients prospectively studied the median dose of thyroxine required to obtain low TSH (median=0.11 mU/l) was 1.41 μg/Kg/day. Following thyroid removal, being the thyroxine dose maintained to pre-surgical levels, median TSH significantly rose to 2.94 mU/l (P=0.031). Low serum TSH (median=0.16 mU/l) was restored in all patients by increasing the median dose by 37% (1.94 μg/Kg/day; P=0.0013). Similarly, in the randomly selected patients the median dose of thyroxine required was higher in thyroidectomized patients (1.83 μg/Kg/day) than in those with nontoxic goitre (1.50 μg/Kg/day; P<0.0001). These data indicate that, both in the same patient and in different groups of patients, the daily dose of thyroxine required to lower plasma TSH is 1/3 higher when the thyroid is absent.