Cationic materials exhibit remarkable anti-inflammatory activity in experimental arthritis models. Our aim was to confirm this character of cationic materials and investigate its possible mechanism. Adjuvant-induced arthritis (AIA) models were used to test cationic materials for their anti-inflammatory activity. Cationic dextran (C-dextran) with different cationic degrees was used to investigate the influence of the cationic elements of materials on their anti-inflammatory ability. Peritoneal macrophages and spleen cells were used to test the expression of cytokines stimulated by cationic materials. Interferon (IFN)-gamma receptor-deficient mice and macrophage-depleted rats were used to examine the possible mechanisms of the anti-inflammatory activity of cationic materials. In AIA models, different cationic materials shared similar anti-inflammatory characters. The anti-inflammatory activity of C-dextran increased with as the cationic degree increased. Cationic materials stimulated interleukin (IL)-12 expression in peritoneal macrophages, and strong stimulation of IFN-gamma secretion was subsequently observed in spleen cells. In vivo experiments revealed that circulating IL-12 and IFN-gamma were enhanced by the cationic materials. Using IFN-gamma receptor knockout mice and macrophage-depleted rats, we found that IFN-gamma and macrophages played key roles in the anti-inflammatory activity of the materials towards cells. We also found that neutrophil infiltration at inflammatory sites was reduced when AIA animals were treated with C-dextran. We propose that cationic signals act through an unknown receptor on macrophages to induce IL-12 secretion, and that IL-12 promotes the expression of IFN-gamma by natural killer cells (or T cells). The resulting elevated systemic levels of IFN-gamma inhibit arthritis development by preventing neutrophil recruitment to inflammatory sites.