A randomized clinical trial was performed in consecutive patients with sporadic nontoxic nodular goiter to compare efficacy and side effects of iodine-131 ((131)I) therapy with suppressive levothyroxine (L-thyroxine) treatment. Sixty-four patients were randomized after stratification for sex and menopausal age to receive (131)I (4.44 MBq/g thyroid; group A) or suppressive L-thyroxine treatment aiming at TSH values between 0.01 and 0.1 mU/L (group B). The main outcome measurements after 2 yr were goiter size by ultrasound, serum thyroid function tests, markers of bone turnover, and bone mineral density (BMD). Fifty-seven patients completed the trial. Goiter size was reduced after 2 yr by 44% in group A and by 1% in group B (P< 0.001). Nonresponders (goiter reduction <13%) were 1 of 29 patients in group A and 16 of 28 patients in group B (P = 0.00001). In responders, goiter reduction in group A (46%) was greater than in group B (22%; P< 0.005). In group A, 45% of patients developed hypothyroidism. In group B, 10 patients experienced thyrotoxic symptoms, requiring discontinuation of treatment in 2 (in 1 because of atrial fibrillation). Markers of bone formation and bone resorption increased significantly in group B, related to a mean decrease of 3.6% of BMD at the lumbar spine after 2 yr (from 1.09 +/- 0.22 to 1.05 +/- 0.23 g/cm(2); P< 0.001), both in pre- and postmenopausal women. No changes in BMD were observed in group A. In conclusion, (131)I therapy is more effective and better tolerated than L-thyroxine treatment in patients with sporadic nontoxic goiter. Suppressive L-thyroxine treatment results in significant bone loss.