Background This study aimed to compare the time to achieve euthyroidism and sustained control of hyperthyroidism after treatment with radioactive iodine (RAI) or long-term methimazole (LT-MMI) in patients with post-RAI relapsed hyperthyroidism. Methods Sixty four patients with recurrence of hyperthyroidism after RAI treatment were randomly assigned to either RAI or LT-MMI treatment. Both groups were followed every 1-3 months in the first year and then every 6 months for a total of 60 months. Results In RAI and LT-MMI groups, mean age was 49.0 +/- 12.1 and 50.1 +/- 14.6 years and time of relapse of hyperthyroidism after previous RAI treatment was 23.2 +/- 18.8 and 20.8 +/- 17.1 months, respectively. At the end of study, in the LT-MMI group, 31 (97%) and 1 (3%) were euthyroid and hypothyroid, respectively; in the RAI group, 8 (25%) patients were euthyroid, whereas 18 (56%), 3 (9.5%) and 3 (9.5%) had overt hypothyroidism, subclinical hypothyroidism and hyperthyroidism, respectively. Mean time to euthyroidism was 9.4 +/- 5.0 months in the RAI group and 3.5 +/- 2.8 months in the LT-MMI group (p < 0.001). Patients in the RAI group spent 77.7 +/- 14.0 percent and those in the LT-MMI group spent 95.2 +/- 5.9 percent of 60 months in the euthyroid state (p < 0.001). Conclusion In patients with post-RAI relapse of hyperthyroidism, LT-MMI treatment was superior to radioiodine because of faster achievement of euthyroidism and more sustained control of hyperthyroidism during 60 months of follow-up.