Diabetic-resistant (DR) BioBreeding (BB) rats developed an erosive hind paw arthritis when immunized with an emulsion of bovine type II collagen (CII) and incomplete Freund's adjuvant. Macroscopic clinical evidence of type II collagen-induced arthritis (CIA) first appeared as periarticular erythema and edema in the hind paws between days 9 and 10 postimmunization with CII. The incidence of CIA was 100% by day 11 in the CII-challenged rats; and CIA severity progressed over a 28-day period with radiographic evaluation revealing focal resorption of bone together with osteophyte formation in the tibiotarsal joint and soft tissue swelling. The histopathology of CIA included an hyperplastic synovium that invaded and eroded articular cartilage at the joint margins, and subchondral bone resorption associated with bone-derived, multinucleated cell-containing granulomatous lesions in the rat hind paw. The corticosteroid, methylprednisolone (medrol), and the nonsteroidal antiinflammatory drug, flurbiprofen (Ansaid), administered at 2 mg/kg (p.o.), suppressed the clinical signs of CIA, and caused 79 to 83% inhibition of hind paw inflammation. However, methylprednisolone, but not flurbiprofen, inhibited the joint pathology in CIA. The antirheumatic drugs, cyclophosphamide (cytoxan, 5 mg/kg, p.o.) and cyclosporin A (CsA, 25 mg/kg, p.o.) suppressed the cartilage erosion in inflamed rat joints, and exerted marked inhibition (89-100%) of hind paw swelling. Methotrexate (0.15 mg/kg, p.o.) treatment reduced hind paw swelling (48%), whereas azathioprine, D-penicillamine (DP) and the oral gold preparation, auranofin, were inactive. Anti-CII antibody titers were completely suppressed by cyclosporin A and cytoxan. Radiographic evidence of protection from bone resorption, osteophyte formation and soft tissue swelling was apparent in the tibiotarsal joints of cytoxan, cyclosporin A, methylprednisolone and methotrexate-treated rat.