Stromal cell-derived factor-1 (SDF-1), also known as CXCL12, and its receptor CXC chemokine receptor 4 (CXCR4) express in various kinds of cells in central nervous system. The SDF-1/CXCR4 signaling pathway is regulated by diverse biological effects. SDF-1 is up-regulated in the ischemic penumbra following stroke and has been known to be associated with the homing of bone marrow cells to injury. However, the effect of SDF-1α/CXCR4 on cytokine production in microglia is mostly unknown. Here, we demonstrated that SDF-1α enhanced IL-6 production in both primary cultured microglia and BV-2 microglia. We further investigated the signaling pathway involved in IL-6 production stimulated by SDF-1α in microglia. SDF-1α increased IL-6 production in both protein and mRNA levels. These effects were attenuated by ERK, phosphatidylinositol 3-kinase (PI3K), NF-κB inhibitors, and IκB protease inhibitor. Stimulation of microglia with SDF-1α also increased Akt and ERK1/2 phosphorylation. In addition, SDF-1α treatment also increased IκB kinase α/β (IKK α/β) phosphorylation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation at Ser276, translocation of p65 and p50 from cytosol to nucleus and κB-luciferase activity. Moreover, SDF-1α-mediated increase of κB-luciferase activity was inhibited by pre-transfection of DN-p85, DN-Akt or DN-ERK2. Increase of IKK α/β phosphorylation and binding of p65 and p50 to the NF-κB element were both antagonized by PI3K and ERK inhibitors. Our results demonstrate a mechanism linking SDF-1α and IL-6, and provide additional support for the notion that SDF-1α plays a regulatory role in microglia activation.