H2-c-fos transgenic (c-fos+) mice are characterized by the inability to raise specific IgG antibodies against immunizing Ag. To examine the contribution of Ag-specific IgG antibody to the development of arthritis, Ag-induced arthritis was produced in c-fos+ mice and their control littermates (c-fos- mice). Intra-articular injection of OVA into c-fos- mice hyperimmunized with OVA induced destructive arthritis with massive lymphocyte infiltration. The c-fos+ mice also developed destructive arthritis comparable in degree with that seen in c-fos- mice. However, joints from the c-fos+ mice had few or no infiltrating lymphocytes. The majority of cells invading the extensively eroded collagenous tissue in the c-fos+ mice had a mesenchymal appearance. These cells, producing excess amounts of c-Fos protein, adhered to and invaded the cartilage matrix when cultured on cartilage slices. These cells, thus, appear to directly cause joint destruction in c-fos+ mice.