Radioactive iodine (I-131) has become the most widely used therapy for patients with hyperthyroidism. caused by Graves' disease in the United States. There remains, however, significant variability among I-131 dosing regimens, and it is clear that most patients ultimately develop hypothyroidism after therapy. To avoid persistent hyperthyroidism, we adopted a high dose I-131 therapy protocol based on measurement of 24-h thyroid I-123 uptake designed to deliver 8 mCi (296 MBq) to the thyroid gland 24 h after I-123 administration. To evaluate the efficacy of this protocol, we reviewed our clinical experience over a 7-yr period. We treated 261 patients (219 women and 42 men) with hyperthyroidism caused by Graves' disease with I-131 [mean dose, 14.6 mCi (540 MEBq)] between 1993 and 1999. Before treatment, 207 (79%) had received an antithyroid drug (109 propylthiouracil and 98 methimazole). We determined their thyroid status 1 yr after treatment in relation to age, pretreatment with an antithyroid drug, pretreatment thyroid size, and dose of I-131 retained in the thyroid 24 h after treatment. Among the 261 patients, 225 (86%) were euthyroid or hypothyroid 1 yr after treatment, and 36 patients (14%) had persistent hyperthyroidism and required a second treatment. The patients who had persistent hyperthyroidism were younger (P < 0.01), had larger thyroid glands (P < 0.01), higher pretreatment thyroid I-123 uptake values (P < 0.01), and higher serum T-4 concentrations (P < 0.01) and were more likely to have taken antithyroid medication before administration of I-131 (P = 0.01). Five of these patients developed transient hypothyroidism, followed by thyrotoxicosis. There was an asymptotic, inverse relationship between the retained dose of I-131 at 24 h and persistent hyperthyroidism, revealing a 5-10% failure rate despite delivery of up to 400 muCi (14.8 MBq)/g. A dose of I-131 that results in accumulation of 8 mCi (296 MBq) in the thyroid gland 24 h after administration is an effective treatment for the majority of patients with Graves' hyperthyroidism. Young patients with larger thyroid glands, higher serum T-4 concentrations, and higher 24-h thyroid I-123 uptake values, and those pretreated with antithyroid medication for greater than 4 months are at higher risk for treatment failure. A higher dose of I-131 may be advisable in such patients.