In this study, we investigate the underlying mechanisms of antibody-mediated inflammation in the brain. We show that immune complexes formed in the brain parenchyma generate a robust and long-lasting inflammatory response, characterized by increased expression of the microglia markers CD11b, CD68 and FcRII/III, but no neutrophil recruitment. In addition to these histological changes, we observed transient behavioural changes that coincided with the inflammatory response in the brain. The inflammatory and behavioural changes were absent in Fc-gamma chain (Fcγ)-deficient mice, while C1q-deficient mice were not different from wild-type mice. We conclude that, in the presence of antigen, antibodies can lead to a local immune complex-mediated inflammatory reaction in the brain parenchyma and indirectly induce neuronal tissue damage through recruitment and activation of microglia via Fcγ receptors. These observations may have important implications for the development of therapeutic antibodies directed against neuronal antigens used for therapeutic intervention in neurological diseases.