The aim of the study was to evaluate the effect of TSH-suppressive therapy with levothyroxine (LT4) on the volume of clinically solitary thyroid nodules, assessing possible correlations between response to therapy and clinical and laboratory parameters. Forty-eight euthyroid patients with a single palpable thyroid nodule (non-autonomous on thyroid scanning, solid or predominantly solid on ultrasonography (US), and benign by fine-needle aspiration biopsy), were followed for 1 year at 3-month intervals. The study group was randomly divided to receive LT4 (200 or 250mcg/day) or placebo, in tablets that were externally identifical. Nodule size was determined by palpation and by US every 6-month. Measurements of T3, T4, TSH, thyroglobulin and anti-thyroid antibodies were performed at baseline and repeated after 3, 6 and 12 months of therapy, whereas thyrotropin-releasing hormone (TRH) test was carried out at 6 months. The number of nodules that decreased in volume on US was not significantly different between the two groups. The mean nodule volume decreased significantly at 6 months in the LT4-treated group, but did not remain significant at 12 months. In the placebo group, the mean nodule volume showed a progressive and significant increase during the study. No correlation was found between clinical and US measurements of the nodules. In the treatment group, nodule size changes were correlated to the scintigraphic characteristics of the nodules. We conclude that LT4 is not effective in reducing the size of most solitary thyroid nodules after 12 months of treatment, although some may shrink or stop to grow after LT4. Further studies are necessary to identify clinical or biochemical variables that could potentially identify the sub-group of responsive nodules.