The levothyroxine suppressive efficacy in benign thyroid nodules treatment is well described in uninodular non-toxic goiter, whereas only few controlled trials enrolled patients with multinodular disease. The aim of the present study is to evaluate the short term effects of levothyroxine treatment in never treated, pre-menopausal women affected by thyroid multinodular disease. Seventy-one pre-menopausal women with thyroid multinodular disease, still presenting normal TSH levels, from Latina area were randomly assigned to a levothyroxine treated or control group. Biochemical and ultrasonography evaluations of thyroid were monitored at the enrollment and after 6, 12 and 24 months of treatment. In the levothyroxine treated group, after 1 year of treatment, thyroid and dominant nodule volume and number of nodules >0.5 mL significantly decreased from a median of 12.0 to 9.8 mL (p <0.001), from 1.0 to 0.5 mL (p <0.001) and from 0.5 to 0, respectively. Conversely, in the control group significant augmented values of these parameters were observed (p =0.007, p <0.001 and p <0.001, respectively). Furthermore, these observations were also confirmed by results obtained after a 24 months follow-up period. Our data support previous observations on the clinical usefulness of L-T(4) treatment in preventing thyroid and nodule volume and nodule numbers growth. These findings confirm the tendency of benign nodular disease toward progression and the efficacy of TSH suppression in preventing its evolution by means of removing the major growth factor for thyroid nodules still responsive to physiological stimuli.