This chapter describes the major principals, methods, and immunization protocols for the induction of a systemic autoimmune arthritis in genetically susceptible murine strains. The model is called proteoglycan-induced arthritis (PGIA) because the antigenic/arthritogenic material is isolated from cartilage. This autoimmune systemic disease is induced by intraperitoneal immunization of either BALB/c or certain C3H colonies with cartilage proteoglycan, an abundant component in articular cartilage. The chapter presents (a) methodological details on how to purify cartilage proteoglycan aggrecan by cesium chloride gradient centrifugation; (b) substitution of this highly purified antigenic/arthritogenic material with a crude cartilage extract obtained from knee joint cartilages removed during joint replacement surgery; and (c) substitution of human cartilage proteoglycan with pig, dog, sheep, or bovine cartilage proteoglycans for arthritis induction. The cartilage proteoglycan aggrecan requires partial deglycosylation, and necessary materials, methods, and protocols are described. In addition, basic methods for measuring antigen-specific T-cell-dependent immune responses, antibody production, serum cytokine levels, and alternative solutions for adoptive transfers are also described.