A myelin-associated neurite outgrowth inhibitor, Nogo-A, plays a key role in inhibition of axonal regeneration following injury and ischemia in the central nervous system (CNS). Because axonal injury is a pathologic hallmark of multiple sclerosis (MS), we have investigated the expression of Nogo-A and its receptor NgR in four MS and 12 non-MS control brains by immunohistochemistry. Nogo-A expression was markedly upregulated in surviving oligodendrocytes at the edge of chronic active demyelinating lesions of MS and ischemic lesions of acute and old cerebral infarction, whereas NgR expression was greatly enhanced in reactive astrocytes and microglia/macrophages in these lesions when compared with their expression in the brains of neurologically normal controls. Nogo-A and NgR were also identified in a subpopulation of neurons. In contrast, Nogo-A was undetectable in reactive astrocytes and microglia/macrophages and NgR was not expressed on oligodendrocytes in any cases examined. Western blot analysis and double labeling immunocytochemistry identified the constitutive expression of NgR in cultured human astrocytes. These results suggest that Nogo-A expressed on oligodendrocytes might interact with NgR presented by reactive astrocytes and microglia/macrophages in active demyelinating lesions of MS, although biologic effects caused by Nogo-A/NgR interaction among glial cells remain unknown.