Antigen presentation within the human central nervous system by the class II histocompatibility DR-antigen may take place at either the brain capillary-endothelial interface or at perivascular cells, such as smooth muscle or pericytes. The present studies employ a new sensitive immunoperoxidase technique, a mouse monoclonal antibody to the human DR-antigen, and microvessels isolated from autopsied human brain. The experiments show that the DR-antigen is readily detectable in human microvasculature of normal brain and is found in the smooth muscle pre-capillary arterioles and capillary pericytes with minimal, if any, staining of capillary endothelium. These results are consistent with the hypothesis that antigen presentation in the CNS occurs primarily at a site immediately distal to the blood--endothelial interface.