Multiple sclerosis is considered to be an immune-mediated disease of the central nervous system, characterized by chronic inflammation, primary demyelination and axonal damage. The mechanisms of demyelination and axonal injury are heterogeneous and complex. One possible mechanism is direct damage of oligodendrocytes and neurons by Class I MHC restricted cytotpxic T-cells. In this study we analyzed the expression of functional MHC class I molecule complex, consisting of α-chain and β2-microglobulin, in a large sample of human autopsy material, containing 10 cases of acute MS, 10 cases of chronic active MS, 10 cases of chronic inactive MS and 21 controls. To examine the expression of MHC class I and II molecules on the different cell-types in brain, we used quantitative immunohistochemical techniques, double staining and confocal laser microscopy scans on paraffin embedded sections. We found constitutive expression of MHC class I molecule on microglia and endothelial cells. A hierarchical up-regulation of MHC class I was present on astrocytes, oligodendrocytes, neurons and axons, depending upon the severity of the disease and the activity of the lesions MHC class II molecules were expressed on microglia and macrophages, but not on astrocytes. These data indicate that in MS lesions all cells of the central nervous system are potential targets for Class I MHC restricted cytotoxic T-cells.