Microglia, the resident macrophages in the central nervous system (CNS), play a pivotal role in innate and adaptive immune responses in the brain. The immune functions of microglia are regulated by cytokines, including interferon (IFN)-gamma, which is a major mediator of macrophage activation. We describe the transcriptional profile of human fetal microglial cells at 1, 6, and 24 h after IFN-gamma treatment. The results show a change in the expression of 405 genes including transcriptionally induced chemokines, IFN-gamma signaling factors, and major histocompatibility complex genes. Our results demonstrate that activation of microglia by IFN-gamma induces proinflammatory T-lymphocyte-related chemokine genes as well as genes involved in antigen presentation. As a result, signals for T-cell infiltration and antigen presentation are produced to allow for microglia-T-cell interactions that likely contribute to defense against invading pathogens. In sum, our results provide a foundation for the molecular mechanisms of the microglial response to IFN-gamma-a key to understanding cell-mediated immunity of the CNS.