Microglia, the resident tissue macrophages of the central nervous system, have a highly differentiated morphology and do not express many of the antigens typically associated with other tissue macrophages. Activation of microglia is associated with a change in morphology and an increase in their repertoire of antigen expression. Microglia become activated in many neuropathological conditions including chronic neurodegenerative diseases and human immunodeficiency virus neuropathology, yet little is known of the mechanisms involved. Here we demonstrate for the first time that microglia can be activated and induced to divide and/or undergo apoptosis via a beta 2-integrin (complement receptor type 3, CR3, Mac-1 or CD11b/CD18) using an anti-CR3 monoclonal antibody (McAb5C6). This antibody, which has been shown to block myelomonocytic recruitment during central nervous system inflammation, is unique in that it can cross the intact blood-brain barrier to activate microglia. Since CR3 not only binds the iC3b component of the alternative complement cascade but also denatured proteins this suggests a potential route for microglia activation in neuropathological conditions.