Prolonged intake of large amounts of iodide has been reported to increase the incidence of goiter and/or hypothyroidism in humans, as well as in animals prone to spontaneous autoimmune thyroiditis (SAT). In the current study, we have investigated the role of dietary iodide on the development of hypothyroidism, as well as thyroiditis, in strains of mice which do not develop SAT. Intake of 0.05% NaI via drinking water for 10 weeks induced hypothyroidism in SJL/J mice as indicated by elevated thyroid stimulating hormone and depressed total thyroxine values in serum, as well as formation of colloidal goiter with an inactive flattened thyroid epithelium. Hypothyroidism did not appear to have an autoimmune basis since only focal mononuclear cell infiltrates were found intrathyroidally, and anti-thyroglobulin Abs or increased organification of iodide were not detected. These phenomena were not observed in similarly treated CBA/J mice suggesting polymorphisms in genes controlling events downstream of iodide uptake by thyrocytes. Interestingly, RT-PCR analysis indicated that unlike CBA/J, SJL/J mice could not down-regulate Na/I symporter gene expression during the NaI treatment. No significant temporal or strain differences were observed regarding the expression of thyroglobulin, pendrin, thyroid peroxidase, DUOX1 and DUOX2 genes following NaI intake. Our results point to the generation of a mouse model for the study of iodine-induced hypothyroidism which does not seem to have an autoimmune basis.