The replacement dose of L-thyroxine was determined in 44 patients with hypothyroidism, 35 with primary thyroidal insufficiency and nine with pituitary failure. In patients with primary hypothyroidism the adequacy of replacement was confirmed by thyrotropin radioimmunoassay values within the normal range. The average daily replacement dose of thyroxine was 169 jug per day (2.25 μg per kilogram), and 89 per cent of the patients were maintained with doses between 100 and 200 μg per day. This amount is significantly less than recommended in current textbooks. The replacement dose correlated with body weight. The average serum thyroxine concentration in treated patients, 8.1 μg per 100 ml, was only slightly higher than that in 55 controls, 7.1 μg. Over 96 per cent of patients receiving replacement had thyroxine concentrations in the generally accepted normal range. The average serum concentration of tri-iodothyronine in treated patients was 130 ng per 100 ml — slightly less than that in control subjects, 140 ng. These data support previous estimates that the bulk of circulating tri-iodothyronine in euthyroid subjects with unstimulated glands is derived from the peripheral conversion of thyroxine. (N Engl J Med 290:529–533, 1974)