The objective of this study is to evaluate the efficacy and potential mechanism of action of type-II collagen bifunctional peptide inhibitor (CII-BPI) molecules in suppressing rheumatoid arthritis in the collagen-induced arthritis (CIA) mouse model. CII-BPI molecules (CII-BPI-1, CII-BPI-2, and CII-BPI-3) were formed through conjugation between an antigenic peptide derived from type-II collagen and a cell adhesion peptide LABL (CD11a237-246) from the I-domain of LFA-1 via a linker molecule. The hypothesis is that the CII-BPI molecules simultaneously bind to MHC-II and ICAM-1 on the surface of APC and block maturation of the immunological synapse. As a result, the differentiation of naïve T cells is altered from inflammatory to regulatory and/or suppressor T cells. The efficacies of CII-BPI molecules were evaluated upon intravenous injections in CIA mice. Results showed that CII-BPI-1 and CIIBPI-2 suppressed the joint inflammations in CIA mice in a dose-dependent manner and were more potent than the respective antigenic peptides alone. CII-BPI-3 was not as efficacious as CII-BPI-1 and CII-BPI-2. Significantly less joint damage was observed in CII-BPI-2 and CII-2 treated mice than in the control. The production of IL-6 was significantly lower at the peak of disease in mice treated with CII-BPI-2 compared to those treated with CII-2 and control. In conclusion, this is the first proof-of-concept study showing that BPI molecules can be used to suppress RA and may be a potential therapeutic strategy for the treatment of rheumatoid arthritis.