In basal conditions, thyroid epithelial cells produce moderate amounts of reactive oxygen species (ROS) that are physiologically required for thyroid hormone synthesis. They are not necessarily toxic because they are continuously detoxified either in the process of hormone synthesis or by endogenous antioxidant systems. Using a rat model of goiter formation and iodine-induced involution, we found that compared to control thyroids, the oxidative stress, assessed by the detection of 4-hydroxynonenal (4-HNE), was strongly enhanced both in hyperplastic and involuting glands. The level of antioxidant defences (glutathione peroxidases and peroxiredoxins) was also up-regulated in both groups, although somewhat less in the latter. Of note, increased oxidative stress came along with an inflammatory reaction, but only in involuting glands suggesting that although antioxidant systems can adequately buffer heavy load of ROS in goiter, it is not necessarily the case in involuting glands. The effects of 15 deoxy-^12,14-prostaglandin J2 (15dPGJ2), an endogenous ligand of PPAR with anti-inflammatory properties, were then investigated in involuting glands. This drug strongly reduced both 4-HNE staining and the inflammatory reaction indicating that it can block iodine-induced cytotoxicity. When experiments were carried out with the PPAR antagonist, bisphenol A diglycidyl ether (BADGE), 15dPGJ2-induced effects remained unchanged suggesting that these effects were not mediated by PPAR. In conclusion, thyroid epithelial cells are well adapted to endogenously produced ROS in basal and goitrous conditions. In iodine-induced goiter involution, the increased oxidative stress is accompanied by inflammation that can be blocked by 15dPGJ2 through PPAR-independent protective effects.