Chronicity of murine allergic arthritis depends on the charge-mediated retention of the cationic antigen in the joint. The authors examined whether arthritis induced with the positively charged antigen amidated bovine serum albumin (aBSA) could be modulated with a nonimmunogenic polycation by competition for anionic retention sites in the joint. Concomitant intraarticular injection of aBSA with the cationic protein protamine chloride (pI approximately 10) strongly reduced the retention of aBSA. Detailed analysis revealed that the retention of aBSA in the noncartilaginous tissues was significantly reduced by protamine, whereas the retention in the highly negatively charged cartilage was completely prevented. Joint inflammation was already significantly suppressed at Day 3 and suppression was still demonstrable at Day 28. Protamine treatment also caused a highly significant reduction in cartilage damage and bone apposition. Control experiments indicated that the suppressive effect of protamine was related to its interference with antigen retention in the joint and not to a mere antiinflammatory action.