The expression of major histocompatibility complex (MHC) class I and II antigens was studied in surgical and postmortem brain biopsy tissue using light and electron microscopic immunocytochemistry. In addition, monoclonal antibodies directed against human macrophages (EBM11) and alpha-smooth muscle actin were applied. It is shown that blood vessel-associated MHC class II immunoreactivity in histologically normal human brain can be localized to a distinct class of cells, termed perivascular cells, which share macrophage but not smooth muscle cell antigen. This immunophenotype, the location in the perivascular space as well as the morphology, frequency and tissue distribution distinguish perivascular cells from pericytes and intraparenchymal microglia. It is suggested that MHC class II positive perivascular cells are a normal constituent of the human cerebral microvasculature. The potential role of these cells in immunological reactions occurring at the blood-brain interface is discussed.