Group A Streptococcus (GAS) produces several immunopotent proteins such as the immunoglobulin-binding protein 35 (Sib35) family, known to be an immunoglobulin G-degrading enzyme of GAS and a CD16-binding protein of GAS, Mac-1-like protein/IdeS. In this study, Sib35 activated mouse B cells and induced the proliferation of B lymphocytes, while it also bound directly to B cells, which enhanced the expression of MHC class II and B7-2. Furthermore, Sib35 induced the differentiation of B cells to immunoglobulin-producing plasma cells and B cell line proliferation. These results suggest that Sib35 functions as a streptococcal mitogen of mouse B cells.