The occurrence of neuroinflammation after spinal cord injury (SCI) is well established, but its function is debated, with both beneficial and detrimental consequences ascribed. A discriminate of the role of neuroinflammation may be the time period after SCI, and there is evidence to favor early neuroinflammation being undesirable, whereas the later evolving phase may have useful roles. Here, we have focused on the inflammatory response in the first 24 hours of SCI in mice. We found elevation of interleukin (IL)-1beta and other cytokines and chemokines within 15 minutes to 3 hours of injury. The early neuroinflammation in SCI is likely to be CNS-derived and involves microglia, as demonstrated by in situ hybridization for IL-1beta in microglia, by an in vitro model of SCI in which elevation of inflammatory cytokines occurs in the absence of a dynamic source of infiltrating leukocytes, and by the correlation of decreased levels of inflammatory molecules and microglia activity in IL-1beta-null mice. Nonetheless, as there are no specific immunohistochemical markers that clearly differentiate microglia from their peripheral counterparts, macrophages, the latter cannot be definitively excluded as participants in early neuroinflammation in mouse SCI. These results of an instantaneous inflammatory response validate approaches to modulate microglia/macrophage activity to improve recovery from SCI.