Expression of Class I (HLA-ABC) and Class II (HLA-Dr; Ia) major histocompatibility (MHC) antigens on endothelial cells and astrocytes was investigated in multiple sclerosis (MS) lesions of variable disease activity and in normal central nervous system (CNS) using immunocytochemical techniques. Findings were correlated to lesion pathology and to the presence and distribution of T cells, T cell subsets, and interleukin-2 (IL-2) receptor-bearing cells. HLA-ABC was present on virtually all endothelial cells in normal and pathologic tissue samples. Ia was absent from controls and was detectable on about 10% of CNS endothelial cells in MS. In normal CNS, astrocytes were Ia-negative and rarely expressed HLA-ABC. In MS, Class I and II MHC-positive astrocytes were found, and both displayed a high frequency in active lesions. Class I-reactive glia were primarily associated with T cell infiltrates and were less common in older lesions in which macrophages predominated. In contrast, Class II-positive astrocytes were found in all active MS lesions independent of the composition of inflammatory cells. Expression of HLA-ABC and Ia molecules on astrocytes in MS lesions could indicate their involvement in local presentation of antigen to cytotoxic (T8+) and helper/inducer (T4+) T cells, respectively. The observed distinct distribution patterns of HLA-ABC and Ia-positive astrocytes might suggest that cytotoxic T8+ cells are operative early during lesion development in MS. This could be followed by a more extensive Class II MHC-restricted helper T cell-mediated immune response which leads to selective destruction of myelin via activated macrophages.