Microglia are the resident immune cells of the central nervous system (CNS) and share many immunological characteristics with peripheral macrophage. Microglia exist in a quiescent state in the healthy CNS, however, upon injury or infection, microglia become activated immune cells. Microglia have been implicated in playing an important role in several neurological diseases that affect the spinal cord, especially multiple sclerosis (MS) and neuropathic pain. However, most studies, which examined the immune response by microglia have been conducted using microglia cultures generated from brain microglia. Therefore, our studies examined the immune response by microglia in the spinal cord compared to the immune response by microglia in the brain. Microglia in the spinal cord of mice expressed higher levels of surface immune molecules than microglia in the brain, and upon virus infection, microglia in the spinal cord expressed higher levels of immune molecules than microglia in the brain. These studies suggest that microglia in the spinal cord may have different immune reactivity than microglia in the brain, which may contribute to spinal cord diseases.