VH replacement occurs through RAG-mediated recombination between a cryptic recombination signal sequence (cRSS) presented in a rearranged VH gene and a 23-bp RSS from an upstream VH gene. VH replacement renews the entire VH coding region and extends the immunoglobulin heavy-chain (IgH) CDR3 regions preferentially with charged amino acids. VH replacement occurs in bone marrow-immature B cells and contributes significantly to the primary B-cell repertoire in humans. However, the biological significance of VH replacement is not clear. Our recent studies revealed elevated frequencies of VH replacement products in different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. Moreover, elevated frequencies of VH replacement products were also found in patients with human immunodeficiency virus or hepatitis C virus infections. These results provide the first clue that VH replacement contributes to autoimmune disease and antiviral immunity, and they also suggest a potential link between viral infection and autoimmune disease.