Microglia, CNS-resident macrophages, serve as scavengers to remove cellular debris and facilitate tissue remodeling in the developing and injured CNS. Little is known as what and how microenvironmental factors mediate the phagocytotic ability of microglia. Our previous study has indicated that treatment with glial cell line-derived neurotrophic factor (GDNF) increased the phagocytotic activity of primary rat microglia possibly through the upregulation of alpha5 integrin. In the present study, ciliary neurotrophic factor (CNTF), which has been reported to be produced by glia, was shown to have stimulatory effect on the phagocytosis of primary rat microglia and mouse microglial cell line BV2. Ca2+ imaging analysis and the application of intracellular calcium chelator BAPTA-AM revealed that CNTF-induced increase in microglial phagocytosis was mediated by a calcium signaling pathway. Furthermore, treatment with CNTF led to an increase in the expression of alphav integrin, which has been reported to be involved in the phagocytosis of the apoptotic cells. In summary, we have provided evidence that CNTF can increase microglial phagocytosis through a calcium-mediated pathway. Our results also suggest that the upregulation of alphav integrin by CNTF could be involved in the increased phagocytotic activity of microglia.