Biosynthesis of thyroid hormones is an oxidative process that generates reactive oxygen species (ROS) and involves thyroperoxidase (TPO) that is one of the main autoantigens involved in autoimmune thyroid diseases. The ectodomain of TPO consists of a large N-terminal myeloperoxidase-like module followed by a complement control protein (CCP)-like module and an epidermal growth factor-like module. The presence of these two additional gene modules suggests that they may play some crucial, hitherto unsuspected role associated with thyroid function. Because the CCP module is a constituent of the molecules involved in the activation of C4 complement component, we investigated the possibility that C4 may bind to TPO and activate the complement pathway in autoimmune conditions. We showed that TPO via its CCP module directly activated complement without any mediation by Ig. We suggested that this additional complement pathway requires the production of ROS and specially hydroxyl radicals that aggregate TPO and oxidize methionines of C4. Moreover, we found, in patients with Hashimoto's thyroiditis, that thyrocytes overexpress C4 and all the downstream components of the complement pathway. These results indicate that TPO has some as yet unknown function, which may contribute along with other mechanisms to the massive cell destruction observed in Hashimoto's thyroiditis. Investigating this complement pathway, therefore, would provide an excellent means of reaching a better understanding of the etiology of other degenerative diseases.