Neonatal exposure to autoantigen is believed to induce effective antigen‐specific T‐cell tolerance in experimental models of autoimmunity. We have identified 120 kDa α‐fodrin autoantigen in an animal model for primary Sjögren's syndrome (SS), that has been determined as a candidate autoantigen in both an animal model and the patients with primary SS. We demonstrate here that neonatal injection of autoantigen induce relevant tolerance when treated with intravenous (i.v.) administration within 24 h after birth, but not with i.v. injection after the thymectomy or with intraperitoneal injection. Autoantigen‐specific T‐cell response was significantly reduced in mice induced neonatal tolerance, and the activation markers of splenic CD4⁺ T cells were down‐regulated in mice treated with neonatal administration. Because we detected that neonatal i.v. injection of autoantigen prevented Th1 response, it is possible that the autoantigen administration within 24 h after birth induce regulatory T cells that had a protective effect against Th1‐mediated autoimmune diseases. These results indicate that the prevention of the spontaneous anti‐120 kDa α‐fodrin response in vivo, by tolerization of the autoantigen‐reactive T cells, blocked the development of autoimmune lesions in an animal model for primary SS.