The balance between effector and regulatory CD4+ T cells plays a key role in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to examine whether the RA autoantigen BiP has epitopes for both effector and regulatory immunities. The proliferation and cytokine secretion of peripheral blood mononuclear cells (PBMCs) from HLA-DR4-positive RA patients in response to BiP-derived peptides were examined by (3)H-thymidine uptake and enzyme-linked immunosorbent assay. As a mouse therapeutic model, a BiP-derived peptide was administered orally to mice with collagen-induced arthritis (CIA). Among the peptides examined, BiP(336-355) induced the strongest proliferation of PBMCs from RA patients, but not from healthy donors. The proliferation of PBMCs in response to BiP(336-355) showed a correlation with clinical RA activity and serum anti-BiP/citrullinated BiP antibodies. In contrast, BiP(456-475) induced interleukin-10 (IL-10) secretion from CD25-positive PBMCs obtained from RA patients and healthy donors without inducing cell proliferation, and it actively suppressed the BiP(336-355)-induced proliferation and proinflammatory cytokine secretion by PBMCs. Oral administration of BiP(456-475) to mice with CIA reduced the severity of arthritis and T cell proliferation and increased the secretion of IL-10 from T cells as well as the number of CD4+CD25+FoxP3+ regulatory T cells. Effector and regulatory T cells recognized different BiP epitopes. The deviated balance toward BiP-specific effector T cells in RA may be associated with disease activity; therefore, BiP-specific effector or regulatory T cells could be a target of new RA therapies.