In response to physical or chemical brain injury, the mammalian central nervous system (CNS) often reacts by evoking astrogliosis. The most prominent feature describing this state is an upregulation of glial fibrillary acidic protein (GFAP). The agent(s) responsible for inducing astrogliosis remains unclear; however, recent observations have shown cytokines may play a pivotal role. During CNS trauma, macrophages and lymphocytes infiltrate the CNS where they are thought to synthesize and secrete cytokines; moreover, activated microglia and reactive astrocytes are known to be capable of cytokine production. We are the first to report that an intracerebral injection of the pleiotropic cytokine, ciliary neurotrophic factor (CNTF), increases astrogliosis and the appearance of activated microglia in the neonatal rat. This response to CNTF was comparable to the response observed in animals receiving a well known pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). Only a moderate increase was observed in the proliferative index of cytokine-injected animals; therefore, we conclude that GFAP is largely upregulated in a pre-existing GFAP negative cell population. Interestingly, coinjections of CNTF and TNF-alpha appeared to act synergistically. Coinjected animals displayed a wave of hypertrophied astrocytes reaching far into the contralateral hemisphere. No contralateral spreading of microglia was observed. This article clearly provides interesting information regarding the regulatory mechanisms that govern astrogliosis and discusses the probable relationship of reactive astrocytes to microglia.