We investigated the early response of microglia with complement and other proteins in well controlled rat central nervous system lesions. A selective neuronal degeneration in the hippocampal CA3 region was induced without direct tissue damage by an intraventricular injection of a small amount of kainic acid. As early as 1 h post injection, complement proteins C1q, C4, and C3 and immunoglobulin(Ig)G were found in the lesioned area. After 2 h, non-specific leakage of other plasma proteins occurred. By 3 h, reactive microglia gathered around the injured pyramidal neurons. Areas surrounding the lesions were depleted, on the other hand, indicating that these reactive microglia had originally resided in and migrated from such vacant areas. Upregulation of ICAM-1 expression by vascular endothelial cells commenced after 6 h. LFA-1-positive leucocytes were, then, accumulated in the vasculature, which was followed by an infiltration of leucocytes into the lesioned brain parenchyma. These results indicate that, following an acute neuronal injury, the response of the humoral factors such as complement proteins and IgG precedes the microglial reaction. Activation of vascular endothelial cells and subsequent infiltration of blood leucocytes occurs much later than the activation and migration of brain resident microglia. The origin of complement proteins and IgG in the lesioned brain parenchyma remains to be determined, although the production of complement proteins by microglia is suggested.