Objective: The association between established hypothyroidism and high cholesterol levels is well known. The aim of the present study was to investigate the effect of thyroxine (T 4 ) administration on cholesterol levels in hypercholesterolemic subjects with TSH levels within the normal range ('highnormal' TSH compared with 'low-normal' TSH). Design and Methods: We determined TSH levels in 110 consecutive patients referred for hypercholesterolemia (serum cholesterol >7.5 mmol/l). Those with 'high-normal' TSH (2.0-4.0 mU/ml) as well as those with 'low-normal' TSH (0.40-1.99 mU/ml) were randomly assigned to receive either 25 or 50 mg T 4 daily for two months. Thus, groups A and B (low-normal TSH) received 25 and 50 mg T 4 respectively and groups C and D (high-normal TSH) received 25 and 50 mg T 4 respectively. Serum T 4 , tri-iodothyronine (T 3 ), TSH, free thyroxine index, resin T 3 uptake and thyroid autoantibodies (ThAab) as well as total cholesterol, high and low density lipoprotein cholesterol (HDL, LDL), and triglycerides were determined before and at the end of the two-month treatment period. Results: TSH levels were reduced in all groups. The most striking effect was observed in group D (TSH levels before: 2.77 Ϯ 0.55, after: 1.41 Ϯ 0.85 mU/ml, P < 0:01). Subjects in groups C and D had a higher probability of having positive ThAabs. A significant reduction in total cholesterol (P < 0:01) and LDL (P < 0:01) was observed after treatment only in group D. In those subjects in group D who were ThAab negative, there was no significant effect of thyroxine on cholesterol levels. Conclusions: Subjects with high-normal TSH levels combined with ThAabs may, in fact, have subclinical hypothyroidism presenting with elevated cholesterol levels. It is possible that these patients might benefit from thyroxine administration.