This paper provides biochemical and histochemical evidence that a fraction of murine brain cells express and synthesize Ia (Immune response-associated) antigens. Both I-A and I-E subregion products are detected on frozen sections of mouse brains by immunoperoxidase staining. Most of these Ia-bearing cells are located in white matter tracts and appear to be intrafascicular oligodendrocytes. In contrast, cells in the gray matter rarely display detectable Ia antigens on their cell surfaces. Specificity of the staining was confirmed by absorption studies. Biochemical evidence for the active synthesis of Ia antigens by brain cells was obtained by immunoprecipitation of [3H]leucine/tyrosine-labeled, NP-40-extracted cell lysates with monoclonal anti-Ia reagent. Both the alpha and beta subunits of Ia antigens were identified by NaDodSO4 electrophoresis. By contrast, anti-mu serum failed to precipitate any product, thus eliminating contaminant B lymphocytes as a source of Ia antigens.