To investigate the long term usefulness of sodium ipodate (Oragrafin) in the management of Graves' hyperthyroidism, we studied the effects of ipodate (500 mg, orally, daily for 23-31 weeks) on serum T3, T4, rT3, and some clinical parameters in five newly diagnosed Graves' hyperthyroid patients. Mean pretreatment serum T3, T4, and rT3 concentrations were 780 ng/dl, 25.4 micrograms/dl, and 118 ng/dl, respectively. One day after the first dose of ipodate, serum T3 decreased by 62% (P less than 0.01), and it was within the normal range thereafter throughout treatment. The serum T4 concentration decreased by 20% (P = 0.09) at 24 h and by 43% (P less than 0.05) at 14 days. Subsequently, serum T4 was 41-65% lower than before treatment throughout the study; rT3 increased 24 h after the first dose of ipodate (118% above baseline; P = 0.1), remained elevated (97-109%) for 10 weeks, and then gradually decreased to the pretreatment level. A marked gain in body weight [5.1 +/- 1.1 (+/- SEM) kg] occurred in all patients. After discontinuation of ipodate, mean thyroid radioiodine (RAI) uptake values increased serially in four patients and were similar to pretreatment values: pretreatment, 74 +/- 6% (+/- SEM); after 7 days, 66 +/- 8%; after 14 days, 71 +/- 7%; after 28 days, 69 +/- 7%. The fifth patients's RAI uptake was 12-16% (vs. a pretreatment value of 48%) from 7-28 days after the end of a 31-week course of ipodate. He remained euthyroid without further treatment for the subsequent 4 months. We conclude that 1) ipodate (500 mg daily) reduces serum T4 and T3 levels as fast and as much as does the 1-g daily dose studied previously; 2) long term use (for 23-31 weeks) of ipodate for the treatment of Graves' hyperthyroidism is clinically feasible; no adverse effects occurred during or after ipodate treatment; and 3) RAI uptake returns to pretreatment levels as early as 7 days after the discontinuation of ipodate. Hence, use of ipodate does not prevent use of 131I therapy for those patients for whom it is otherwise desirable.