Some studies have suggested that increasing the daily dose of anti-thyroid drugs might improve long-term remission rates of Graves' disease. Therefore, this question was addressed in a prospective multicenter trial involving 18 thyroid clinics in Europe, mostly in iodine-deficient or moderately iodine-sufficient regions. Five hundred and nine patients with Graves' hyperthyroidism were enrolled in a prospective randomized trial comparing the remission rates after treatment with methimazole (MMI) at two fixed dosages (10 vs. 40 mg) with levothyroxine supplementation. The treatment and follow-up periods lasted 12 months each. Sixty and seven-tenths percent of the recruited patients (total, 309; 153 in the 10 mg, 156 in the 40 mg group) were finally evaluated, and comparison of the two groups showed that they were well matched with respect to a wide range of variables, including parameters of thyroid function. With 10 mg MMI daily, 68.4% of the patients were euthyroid after 3 weeks, and 84.9% after 6 weeks, compared to 83.1% and 91.6%, respectively, with the use of 40 mg MMI daily. TSH receptor antibodies decreased similarly in the two groups, 25% of patients in the 10 mg group, and 30% in the 40 mg group still being TSH receptor antibodies positive after 12 months. One hundred and ninety six (63.4%) of the 309 patients achieved remission of Graves' disease. The two MMI doses were equally effective; 35.9% compared to 37.2% of patients treated with 10 and 40 mg MMI, respectively, had relapses. There was no difference in the length of the time interval between stopping treatment and recurrence between the two groups. However, the rate of adverse drug reactions increased from 39/251 (15.5%) in the 10 mg group to 67/258 (26.0%) in the 40 mg group (P < 0.01). Under conditions of iodine deficiency or borderline sufficient iodine supply, 40 mg MMI daily will render more patients with Graves' disease euthyroid within the first 6 weeks of treatment than 10 mg daily, but at the expense of an increased rate of adverse reactions. However, patients treated with 40 mg MMI daily for 1 yr have no higher chance of remission than patients treated with 10 mg. It does not appear justified at present to recommend MMI doses higher than required for the control of hyperthyroidism (with the goal of immunosuppression).