Oral tolerance means a diminished immune response to previously fed antigens. Repeated oral administrations of type II collagen (CII) induce oral tolerance and inhibit the development of collagen-induced arthritis (CIA). Dendritic cells (DCs) in the gut-associated lymphoid tissue (GALT) take up the CII and then present it to T cells to generate regulatory T cells (Tregs), which induce systemic immune tolerance to CII. Inhibitory cytokines, such as transforming growth factor (TGF)-beta and interleukin (IL)-10, and several immune regulatory molecules, including indoleamine 2,3-dioxygenase (IDO) and retinoic acid, play an important role in Treg generation. Each DC subset may play different roles, and CD11c+CD11b+DCs and IDO+DCs are important in the generation of antigen-inducible Tregs in CII oral tolerance. Upon stimulation with the antigen involved in its generation, Treg is activated and regulates the immune response through inhibitory cytokine production, cell-to-cell contact-dependent mechanisms, DC modification, and bystander suppression. The DCs and Tregs are deeply involved in oral tolerance through reciprocal interactions. Several clinical trials have been conducted in RA patients to examine the efficacy of CII oral tolerance. An understanding the mechanism of oral tolerance to CII would give clinicians new insights into the development of natural immune tolerance and new therapeutic approaches for the treatment of autoimmune diseases.