Iodine (I) is essential for normal thyroid function, and the majority of subjects tolerate a wide range of dietary levels. However, a subset of individuals upon exposure to normal or elevated levels of I develop thyroid dysfunction and autoimmunity. In this double blind trial, we evaluated efficacy and tolerability of low dose I in adults with euthyroid, diffuse, endemic goiter. Sixty-two subjects were randomly assigned I (0.2 mg/day) or placebo for 12 months. After termination of therapy, both groups were followed for a further 6 months. Thyroid sonography and determinations of thyroid-related hormones, urinary I excretion per 24 h, and thyroid antibodies were carried out at baseline and at 3, 6, 9, 12, 15, and 18 months. Markedly elevated urinary I values were found during therapy in subjects receiving I (32 at baseline vs. 213 micrograms/24 h at 12 months; P = 0.0001) compared to placebo (34 and 33 micrograms/24 h, respectively; P < 0.0001 vs. I). I substantially reduced thyroid volume (29 vs. 18 mL at 12 months; -38%; P = 0.0001), and at 18 months, the therapeutic effect was sustained. In the placebo group, no significant changes were observed. High microsomal and thyroglobulin autoantibody titers were present in 3 of 31 (9.7%) subjects receiving I, and I-induced hypo- and hyperthyroidism developed in 2 and 1, respectively. Fine needle biopsy revealed marked lymphocytic infiltration in all 3 cases. After withdrawal of I, thyroid dysfunctions spontaneously remitted, and antibody titers as well as lymphocytic infiltration decreased markedly. Follow-up of these 3 subjects for an additional 2 yr showed normalization of antibody titers in 2. Thus, among subjects with endemic goiter, low dose I successfully normalized thyroid volume and body I supplementation; nevertheless, reversible I-induced thyroid dysfunctions and autoimmunity were observed in nearly 10% of the subjects.