Lipopolysaccharide (LPS) has been used as a reagent for a model of systemic inflammatory response. Ribosomal protein S3 (rpS3) is a multi-functional protein that is involved in transcription, metastasis, DNA repair, and apoptosis. In the present study, we examined the changes of rpS3 immunoreactivity in the mouse hippocampus after systemic administration of 1 mg/kg of LPS. From 6 h after LPS treatment, rpS3 immunoreactivity was decreased in pyramidale cells of the hippocampus proper (CA1-CA3 regions) and in granule cells of the dentate gyrus. At this point in time, rpS3 immunoreactivity began to increase in non-pyramidal cells and non-granule cells. From 1 day after LPS treatment, rpS3 immunoreactivity in pyramidal and granule cells was hardly detected; however, strong rpS3 immunoreactivity was shown in non-pyramidal and non-granule cells. Based on double immunofluorescence staining for rpS3/ionized calcium-binding adapter 1 (Iba-1, a marker for microglia) and glial fibrillary acidic protein (GFAP, a marker for astrocytes), strong rpS3 immunoreactivity was expressed in Iba-1-immunoreactive microglia, not in GFAP-immunoreactive astrocytes, at 1 and 2 days after LPS treatment. These results indicate that rpS3 immunoreactivity changes only in pyramidal and granule cells, and rpS3 is expressed only in activated microglia after LPS treatment: this may be associated with the neuroinflammatory responses in the brain.