We previously reported that a combination of 4 monoclonal antibodies (mAbs) (cocktail A) to type II collagen (CII), including immunoglobulin G (IgG)2b (C2B-9 and C2B-14) and IgG2a (C2A-7 and C2A-12), induced arthritis in DBA/1J mice. In this study, we found that C2B-9 and C2A-7 as well as C2B-14 and C2A-12 recognized the same or similar epitopes on CII. Based on these data, we hypothesized that the combination of more than 3 mAbs recognizing different epitopes on CII may more efficiently induce arthritis. Therefore, in addition to C2B-9 and C2B-14, which show high binding activity to CII compared with C2A-7 and C2A-12, we developed two more mAbs including IgG2b (C2B-17) and IgG2a (C2A-16), to make a new cocktail (cocktail B) consisting of these 4 mAbs. To compare the ability of cocktail B to induce arthritis with cocktail A, DBA/1J mice were injected with these cocktails. The results showed that cocktail B was able to induce more severe arthritis than cocktail A, especially more markedly affecting rear paws. Histologically, there was more marked proliferation of synovial tissues, massive infiltration by inflammatory cells, and severe destruction of cartilage and bone in mice treated with cocktail B than with cocktail A. Collectively, the new combination of 4 mAbs recognizing different respective epitopes appears to effectively induce arthritis in mice. Thus, the results may provide insights into the selection of mAbs associated with the development of arthritis.