Severe iodine deficiency may impair thyroid hormone synthesis and cause a compensatory increase in H2O2 concentration in thyrocytes. This may result in more prolonged exposure to oxygen-free radicals, which in turn may extend reactive oxygen species (ROS)-mediated oxidative damage including DNA, induce mutations, and possibly contribute to degenerative changes in tissues. High levels of cell proliferation and higher replication rates during thyroid enlargement may also prevent mutation repair and implement mutations into the genome. A history of benign thyroid diseases, mostly goiter and nodules, and long-term residency in iodine-deficient areas have been considered as established risk factors for thyroid cancer. Our experimental data showed the availability of an effective mechanism to regulate antioxidative response in the thyroid glands of severely iodine deficient rats by adaptive increases in antioxidant enzymes (cGPx, SOD and CAT) during severe iodine deficiency. Our studies on high-school children from a severely iodine-deficient area indicated the presence of oxidative activity and enhancement of free radical reactions in severely plus moderately iodine deficient goitrous children, and suggested that goiter development is more likely to occur in individuals having lower status of antioxidant enzymes and selenium.