We have recently demonstrated that a novel type of keratan sulfate proteoglycan (KSPG) identified by the monoclonal antibody (mAb) 5D4 is expressed on ramified microglia but downregulated coincident with T-cell-mediated autoimmune inflammation of the spinal cord in Lewis (LEW) rats. In this study we show by immunocytochemistry and Western blot analysis that various inbred rat strains differ significantly in their constitutive expression of KSPG on ramified microglia in the normal CNS. Microglial KSPG was high in LEW and Fischer 344 rats but low in DA, Brown Norway (BN), and PVG rats. The KSPG low-expressing strains exhibited constitutive expression of major histocompatibility complex (MHC) class II antigens on ramified microglia that was not detectable in the KSPG high-expressing strains. Thus, an inverse correlation between constitutive KSPG and MHC class II expression was present. The KSPG-low-/MHC class II-positive phenotype is associated with resistance to experimental autoimmune encephalomyelitis in BN and PVG, but not DA rats. These findings suggest a significant impact of genetic factors on the molecular differentiation of resident macrophages in the CNS.