An antibody response to defined epitopes located on the triple helical portion of type II collagen (CII) is associated with the development of collagen-induced arthritis (CIA) and rheumatoid arthritis (RA). Monoclonal antibodies to epitopes associated with arthritis, but not antibodies specific for epitopes not associated with arthritis, induce arthritis in mice, the so-called collagen antibody induced arthritis (CAIA) model. We have selected monoclonal IgG antibodies specific for four well-defined major epitopes on triple helical CII, the C1, J1, D3 and U1 epitopes. These antibodies bind the epitopes specifically as determined using recombinant or synthetic triple helical epitopes. They are encoded from somatically mutated V genes. They all bind cartilage in vivo in normal mice. All of the antibodies induce mild arthritis after injection intravenously and if injected as a cocktail they induce severe clinical arthritis. Intravenous injection of a total of 4 mg antibodies (0.5 mg antibodies per clone) induced arthritis in several different mouse strains without any secondary immune stimulus and intraperitoneal injection of LPS 7 days later dramatically raised the severity. Thus, this method is recommended as a new protocol for the induction of CAIA. © 2005 Elsevier B.V. All rights reserved.