Immunization with chondroitinase ABC-digested fetal human cartilage proteoglycan and Freund's complete adjuvant induced polyarthritis and ankylosing spondylitis in female BALB/c mice. The initial external symptoms of the joint inflammation were swelling and redness. This was associated with edema of the synovium and periarticular tissues and gross proliferation of cells, which reached a peak during weeks 7-9 of the experiment. Mononuclear cell infiltration, with perivascular concentration and occlusion of small vessels, was common. Synovitis increased in severity, villous pannus developed, and erosions of bone, articular cartilage, and occasionally, growth plate were observed. The lumbar spine and the proximal intervertebral discs of the tail also exhibited inflammatory and degenerative changes. As the arthritis progressed, sometimes with acute inflammatory exacerbations, more joints became involved and, by the sixteenth to the twentieth weeks of the experiment, a progressive polyarthritis, with gross joint deformities and restricted function, developed in the majority of the limb joints. Clinical and morphologic features of the disease correlated well with radiologic analysis and with an increased deposition of 99mTc-methylene diphosphonate (determined by radionuclide imaging). The development of this arthritis was accompanied by the expression of cell-mediated and humoral immunity to the immunizing antigen. However, this immunity was also observed, although it was generally less well developed, in mice that received the intact or digested proteoglycan without adjuvant. These mice did not usually develop arthritis. Control mice that received only adjuvant did not develop arthritis.