OBJECTIVE Previous studies of leptin in thyrotoxic human subjects have been short-term and cross-sectional. We have measured serum leptin concentrations in thyrotoxic patients in order to study the influence of endogenous thyroid hormones on the relationship between serum leptin and fat mass. DESIGN patients, measurements: In 10 tasting thyrotoxic patients (8 females, 2 males, mean age: 51 years) we measured serum leptin (mu g/l), total thyroxine (TT4), total triiodothyronine (TT3), thyrotropin (TSH) and by Dual Energy X-ray Absorptiometry (DEXA) total fat mass (TFM, kg) at time of diagnosis (0 months, baseline) and during 12 months treatment with thiamazole. For comparison 16 fasting thiamazole-treated euthyroid patients (14 females, 2 males, mean age: 38 years) were studied after one year follow-up (26 month (15-48)) and 18 normal controls (12 females, 6 males, mean age: 39 years). RESULTS The serum leptin concentration was 9.1 (1.3 mu g/l (mean (SEM) in the thyrotoxic patients and increased significantly to 16.0 (1.3 mu g/l (P<0.0005) after 12 months treatment compared to both normal subjects and their own baseline, There was a significant correlation between serum leptin concentration and TFM in the normal control group (r = 0.79, P < 0.00009), in the thiamazole-treated euthyroid group (r = 0.85, P < 0.00003) and in the baseline thyrotoxic group (r = 0.84, P < 0.002) but the serum leptin/TFM ratio increased significantly during 12 months of antithyroid drug treatment from 0.34 (1.2 mu g/l/kg to 0.53 (1.2 mu g/l/kg (P< 0.03). CONCLUSION The thiamazole-treated thyrotoxic patients increased their serum leptin concentrations during 12 months antithyroid drug treatment without a significant corresponding degree of changes in TFM as expected from normal controls. It is suggested that the metabolic state in thyrotoxic patients can influence the regulation of serum leptin concentrations without any associated changes in TFM.