It is unclear whether organ-specific autoantigens are critical for the development of primary Sjögren’s syndrome (SS). A 120-kilodalton organ-specific autoantigen was purified from salivary gland tissues of an NFS/sld mouse model of human SS. The amino-terminal residues were identical to those of the human cytoskeletal protein α-fodrin. The purified antigen induced proliferative T cell responses and production of interleukin-2 and interferon-γ in vitro. Neonatal immunization with the 120-kilodalton antigen prevented the disease in mice. Sera from patients with SS reacted positively with purified antigen and recombinant human α-fodrin protein, whereas those from patients with systemic lupus erythematosus and rheumatoid arthritis did not. Thus, the immune response to 120-kilodalton α-fodrin could be important in the initial development of primary SS.