ABSTRACT: INTRODUCTION: Cartilage oligomeric matrix protein (COMP) is a homopentameric protein in cartilage. The development of arthritis, like collagen-induced arthritis (CIA), involves cartilage as a target tissue. We have investigated the development of CIA in COMP-deficient mice. METHODS: COMP-deficient mice in the 129/Sv background were backcrossed for 10 generations against B10.Q mice, which are susceptible to chronic CIA. COMP-deficient and wild-type mice were tested for onset, incidence, and severity of arthritis in both the collagen and collagen antibody-induced arthritis models. Serum anti-collagen II and anti-COMP antibodies as well as serum COMP levels in arthritic and wild-type mice were measured by enzyme-linked immunosorbent assay. RESULTS: COMP-deficient mice showed a significant early onset and increase in the severity of CIA in the chronic phase, whereas collagen II-antibody titers were similar in COMP-deficient and wild-type controls. COMP antibodies were not found in wild-type mice. Finally, COMP-deficient and wild-type mice responded similarly to collagen antibody-induced arthritis, indicating no difference in how collagen II antibodies interact with COMP-deficient cartilage during the initial stages of arthritis. CONCLUSIONS: COMP deficiency enhances the early onset and development of chronic arthritis but does not affect collagen II autoimmunity. These findings accentuate the importance of COMP in cartilage stability.