The ultrastructural relation between microglial cells and cerebral blood vessels was studied in rat brains by immune electron microscopy using antibodies against the common leukocyte antigen (Oxl), the complement receptor 3 (Ox42), and against class I and class II histocompatibility antigens (MHC antigens; Ox3, Ox6, Oxl8, and I1-69). Microglial cell processes were found incorporated between the astrocytic foot processes of the glia limitans in 4–13% of cerebral microvessels. After intravenous injection of γ-interferon, either alone or in combination with tumor necrosis factor, these microglial cell processes expressed classes I and II MHC antigens. Studies in (Lewis × DA)F1-DA bone marrow chimeras demonstrated that these cell processes belonged to resident microglia. This study suggests that microglial cells may play an important role in antigen recognition at the blood-brain barrier.