OBJECTIVE This study aimed to evaluate the effects of radioiodine ((131)I), alone or in combination with lithium, on thyroid volume and the prevention of radioiodine-induced thyrotoxicosis. This is the first clinical trial including only patients with multinodular goitre, normal TSH values and negative anti-thyroid auto-antibodies at baseline. METHODS Eighty consecutive patients were randomised to receive (131)I plus lithium (group I+L) or (131)I alone (group I). Thyroid ultrasonography and biochemical analyses were performed at baseline and at 1, 3, 6, 12 and 24 months after treatment. RESULTS At 1-4 weeks after treatment, (131)I-induced hyperthyroidism was observed in 58.8% of patients and was prevented by lithium administration. A low incidence of hypothyroidism (19%) was recorded at 24 months, whereas up to 44% of patients developed anti-thyroid antibodies. A significant reduction in thyroid volume was observed after (131)I, with a mean decrease of 47.2% (median 48.2%) at 24 months, without differences between the groups. Moreover, it was shown that the decrease in thyroid volume after (131)I was also due to the significant shrinkage of thyroid nodules. CONCLUSIONS This demonstrates that adjunctive lithium is able to reduce radioiodine-induced hyperthyroidism. Therefore, such treatment appears to be safe in older patients and those with underlying cardiovascular disease. In the present large series, (131)I therapy was demonstrated to be highly effective in reducing thyroid and nodular volume even in patients treated with low (131)I doses (2.5 MBq/ml of thyroid tissue), further supporting the view that radioiodine therapy represents a real alternative to surgery.